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Science and Judgment in Risk Assessment (1994)

Chapter: Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment

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Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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Appendix
D
Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment

Notice

THIS DOCUMENT IS A PRELIMINARY DRAFT. Until formal announcement by the U.S. Environmental Protection Agency is made in the Federal Register, the policies set forth in the 1986 Guidelines for Carcinogen Risk Assessment, as they are now interpreted, remain in effect. This working paper does not represent the policy of the U.S. Environmental Protection Agency with respect to carcinogen risk assessment.

Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, D.C.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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Disclaimer

This document is a draft working paper for review purposes only and does not constitute Agency policy. Mention of trade names or commercial products does not constitute endorsesement or recommendation for use.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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Contents

List of Figures

387

Authors and Contributors

387

PREAMBLE

388

1.

INTRODUCTION

394

 

1.1.

PURPOSE AND SCOPE OF THE GUIDELINES

394

 

1.2.

TYPES OF DATA USED IN CARCINOGENICITY ASSESSMENT

395

 

1.3.

ORGANIZATION OF THE GUIDELINES

396

 

1.4.

APPLICATION OF THE GUIDELINES

396

2.

HAZARD ASSESSMENT

397

 

2.1.

INTRODUCTION

397

 

2.2.

INTEGRATING DATA FOR HAZARD ASSESSMENT

398

 

2.3.

ANALYSIS OF HUMAN DATA

398

.

 

2.3.1

Epidemiologic Studies

398

     

2.3.1.1

Exposure Focus

399

     

2.3.1.2

Types of Epidemiology Studies

400

   

2.3.2.

Elements of Critical Analysis

400

     

2.3.2.1

Exposure

400

     

2.3.2.2

Population Selection Criteria

401

     

2.3.2.3

Confounding Factors

402

     

2.3.2.4

Sensitivity

402

     

2.3.2.5

Criteria for Causality

403

 

2.4.

SUMMARY OF HUMAN EVIDENCE

404

   

2.4.1.

Category 1

405

   

2.4.2.

Category 2

405

     

2.4.3.

Category 3

405

     

2.4.4.

Category 4

406

 

2.5.

ANALYSIS OF LONG-TERM ANIMAL STUDIES

406

   

2.5.1.

Significance of Response

406

   

2.5.2.

Historical Control Data

407

   

2.5.3.

High Background Tumor Incidence

408

   

2.5.4.

Dose Issues

408

   

2.5.5.

Human Relevance

409

 

2.6.

ANALYSIS OF EVIDENCE RELEVANT TO CARCINOGENICITY

409

   

2.6.1.

Physical-Chemical Properties

409

   

2.6.2.

Structure-Activity Relationships

410

   

2.6.3.

Metabolism and Pharmacokinetics

411

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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2.6.4.

Mechanistic Information

412

.

   

2.6.4.1

Genetic Toxicity Tests

413

.

   

2.6.4.2

Other Short-Term Tests

415

.

   

2.6.4.3

Short Assays for Carcinogenesis

416

     

2.6.4.4

Evaluation of Mechanistic Studies

416

 

2.7.

SUMMARY OF EXPERIMENTAL EVIDENCE

418

   

2.7.1.

Category 1

419

   

2.7.2.

Category 2

420

   

2.7.3.

Category 3

420

   

2.7.4.

Category 4

421

 

2.8.

HUMAN HAZARD CHARACTERIZATION

421

   

2.8.1.

Purpose and Content of Characterization

421

   

2.8.2.

Weight of Evidence for Human Carcinogenicity

421

.

   

2.8.2.1

Descriptors

424

     

2.8.2.2

Examples of Narrative Statements

425

3.

DOSE-RESPONSE ASSESSMENT

427

 

3.1.

PURPOSE AND SCOPE OF DOSE-RESPONSE ASSESSMENT

427

 

3.2.

ELEMENTS OF DOSE-RESPONSE ASSESSMENT

428

   

3.2.1.

Response Data

428

   

3.2.2.

Dose Data

429

     

3.2.2.1

Base Case—Few Data

430

     

3.2.2.2

Pharmacokinetic Analyses

431

     

3.2.2.3

Additional Considerations for Dose in Human Studies

431

 

3.3.

SELECTION OF QUANTITATIVE APPROACH

432

   

3.3.1.

Analysis in the Range of Observation

433

   

3.3.2.

Extrapolation

435

   

3.3.3.

Issues for Analysis of Human Studies

436

   

3.3.4.

Use of Toxicity Equivalence Factors (TEF)

436

 

3.4.

DOSE-RESPONSE CHARACTERIZATION

437

4.

EXPOSURE ASSESSMENT

438

5.

CHARACTERIZATION OF HUMAN RISK

439

 

5.1.

PURPOSE

439

 

5.2

APPLICATION

439

 

5.3.

CONTENT

439

   

5.3.1.

Presentation and Descriptors

439

   

5.3.2.

Strengths and Weaknesses

440

6.

REFERENCES

440

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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List Of Figures

Figure 1

 

423

Authors And Contributors

This draft working paper was prepared by an intra-Agency EPA working group chaired by Jeanette Wiltse of the Office of Health and Environmental Assessment.

Working Paper For Considering Draft Revisions To The U.S. Epa Guidelines For Cancer Risk Assessment

This working paper identifies cancer risk assessment issues that some Agency scientists have been discussing as a basis for possible proposed revisions to EPA's 1986 Guidelines for Carcinogen Risk Assessment. The working paper is being given to other scientists to obtain early comment on the many issues that remain undeveloped or are still under discussion. The working paper is not a proposal. It has not been reviewed or approved by any EPA official, and the proposal that is eventually approved is likely to be very different in many respects from this working paper. When proposed revisions are ready, EPA will publish them in the Federal Register for public comment.

Until formal announcement by the U.S. Environmental Protection Agency is made in the Federal Register, the policies set forth in the 1986 Guidelines for Carcinogen Risk Assessment, as they are now interpreted, remain in effect. This working paper does not represent the policy of the U.S. Environmental Protection Agency with respect to carcinogen risk assessment.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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Preamble

The United States Environmental Protection Agency (EPA) 1986 guidelines on carcinogenic risk assessment (51 FR 33992, September 24, 1986)) stated that, ''… [a]t present, mechanisms of the carcinogenesis process are largely unknown …". This is no longer true. The last several years have brought research results at an explosive pace to elucidate the molecular biology of cancer. This new knowledge is only beginning to be applied in generating data about environmental agents. Guideline revisions are intended to be flexible and open to the use of such new kinds of data even though the guidelines cannot fully anticipate the future forms that carcinogenicity testing and research may take. At the same time, the guidelines address assessment of the kinds of data that are the current basis of carcinogenicity assessment as a result of the past two decades of development of the science of risk assessment. Because methods and knowledge are expected to change more rapidly than guidelines can practicably be revised, most of the Agency's development of procedures for cancer risk assessment will henceforth be accomplished through publication of technical work performed under the aegis of the Agency's Risk Assessment Forum. The technical documents of the Forum are developed by a process that engages the general scientific community with EPA scientists. The documents are made available for public examination as well as for scientific peer review through the EPA Science Advisory Board and other groups. The Forum sponsored two workshops in which areas of potential revision to the guidelines were discussed by scientists from public and private groups. (USEPA, 1989a; USEPA, 1991a).

Major Changes from 1986 Guidelines

Revisions in this working paper differ in many respects from the Agency's 1986 guidelines. The reasons for change arise from new research results, particularly about the molecular biology of cancer, and from experience using the 1986 guidelines.

One area of change is increased emphasis on providing characterization discussions for each part of a risk assessment (hazard, dose-response, exposure, and risk assessments). These serve to summarize the assessments with emphasis on explaining the extent and weight of evidence, major points of interpretation and rationale, strengths and weaknesses of the evidence and analysis, and alternative conclusions that deserve serious consideration.

Two other areas of major change are in:

(1)

the way the weight of evidence about an agent's1 hazard potential is expressed; and

1The term "agent" is used throughout (unless otherwise noted) for a chemical substance, mixture, or physical or biological entity that is being assessed.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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(2)

approaches to dose-response assessment.

1. To express the weight of evidence for carcinogenic hazard potential, the 1986 guidelines provided tiered summary rankings for human studies and for animal bioassays. These summary rankings of evidence were integrated to place the overall evidence in alphanumerically designated classification groups A through E, Group A being associated with the greatest probability of carcinogenicity. Other experimental evidence played a modulating role for ranking. Considerations such as route of exposure (e.g., oral versus inhalation) and mechanism of action were not explicitly captured in a characterization.

These working revisions take a different approach. The idea of summary ranking of individual kinds of evidence is retained and expanded, but these are integrated differently and expressed in a narrative weight of evidence characterization statement. {Whether an alphanumerical rating will be a part of this statement is an unresolved issue still under discussion at EPA.}

The narrative statement is preceded by summary rankings of human observational evidence and of all experimental evidence. The summary ranking for experimental evidence is composed of long-term animal bioassay evidence and all other experimental evidence on biological and chemical attributes relevant to carcinogenicity. This stepwise approach anticipates marshalling evidence and organizing conclusions as analysis proceeds, for convenience of consideration. It also gives explicit weight to certain kinds of experimental evidence that previously were considered in a "modulating" role.

The narrative statement provides a place to describe evidence by route of exposure and to describe the hazard assessment and dose-response implications of mechanism of action data in characterizing the overall weight of evidence about human carcinogenicity.

2. The approach to dose-response assessment is another area of major change. It calls for a stepwise analysis that follows the conclusions reached in the hazard assessment as to potential mechanism of action. Two steps divide the analysis into modeling in the range of observed data and analysis of dose-response below the range of observed data.

{The process for combining all the findings relevant to human carcinogenic potential is a matter of continuing discussion at EPA. This working paper presents one of a number of suggested approaches. The objective is to be integrative and holistic in judging while at the same time giving guidance to junior scientists in various disciplines about how to marshal and present findings.}

{How to use mechanistic information in dose-response assessment is incom-

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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pletely developed in these working paper. Specific issues are pointed out in later sections.}

Perspectives for Carcinogenicity Assessment

The following paragraphs summarize part of the current picture of the events in the process of carcinogenesis. Most of the research cited was conducted with experimental approaches not commonly used to study environmental agents. Nevertheless, as this picture is elaborated, more experimental approaches will become available for testing specific mechanisms of action of environmental agents. Even before this happens as a general forward step, information currently available for some agents can be interpreted in light of this picture to make informed inferences about the role the agent may play at the molecular level.

Normally, cell growth in tissues is controlled by a complex and incompletely understood process governing the occurrence and frequency of mitosis (cell division) and cellular differentiation. Adult tissues, even those composed of rapidly replicating cells, maintain a constant size and cell number (Nunez et al., 1991). This appears to involve a balance among three cell fates: (1) continued replication or loss of ability to replicate, followed by (2) differentiation to take on a specialized function or (3) programmed cell death (Raff, 1992; Maller, 1991; Naeve et al., 1991; Schneider et al., 1991; Harris, 1990). As a consequence of either the inactivation of processes that lead to differentiation or cell death, replicating cells may have a competitive growth advantage over other cells, and neoplastic growth clonal expansion can result (Sidransky et al., 1992; Nowell, 1976).

The path a cell takes is determined by a timed sequence of biochemical signals. Signal transduction pathways, or "circuits" in the cell, involve chemical signals that bind to receptors, generating further signals in a pathway whose target in many cases is control of transcription of a specific set of genes (Hunter, 1991; Cantley et al., 1991; Collum and Alt, 1990). A cell produces its own constituent receptors, signal transducers, and signals, and is subject to signals produced by other cells, either neighboring ones or distant ones, for instance, in endocrine tissues (Schuller, 1991). In addition to hormones produced by endocrine tissues, numerous soluble polypeptide growth factors have been identified that control normal growth and differentiation (Cross and Dexter, 1991; Wellstein et al., 1990). The cells responsive to a particular growth factor are those that express transmembrane receptors that specifically bind the growth factor.

One can postulate many ways to disrupt this kind of growth control circuit, including increasing or decreasing the number of signals, receptors, or transducers, or increasing or decreasing their individual efficiencies. In fact, human genetic diseases that make individuals cancer-prone involve mutations that appear to have some of these effects (Hsu et al., 1991; Srivastava, 1990; Kakizuka et al., 1991). Tumor cells found in individuals who do not have genetic disease

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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have also been shown to have mutations with these consequences (Salomon et al., 1990; Bottaro et al., 1991; Kaplan et al., 1991; Sidransky et al., 1991). For example, neoplastic cells of individuals with acute promyelocytic leukemia (APL) have a mutation that blocks cell differentiation in myeloblasts that normally give rise to certain white cells in blood. The mutation apparently alters a receptor that normally responds positively to a differentiation signal. Patients with APL involving this mutation have been successfully treated by oral administration of retinoic acid, which functions as a chemical signal that apparently overrides the effect of the mutation, and drives the neoplastic cells to stop replicating and differentiate. This "differentiation therapy" demonstrates the power conveyed by understanding the growth control signals of these cells (Kakizuka et al., 1991; de The et al., 1991).

Several kinds of gene mutations2 have been found in human and animal cancers. Among these are mutations in genes termed tumor susceptibility genes. One kind, mutations that amplify positive signals to replicate or avert differentiation, are termed oncogenes (proto-oncogenes in their normal state). Another kind are mutations in genes involved in generating negative growth signals, termed tumor suppressor genes (Sager, 1989). Damage to these two kinds of genes has been found in cells of tumors in many animal and human tissues including the sites of the most frequent human cancers (Bishop, 1991; Malken et al., 1990; Srivastava et al., 1990; Hunter, 1991). The functions and deoxyribonucleic acid (DNA) base sequences of the genes are highly conserved across species in evolution (Auger et al., 1989a, b; Kaplan, 1991; Hollstein et al., 1991; Herschman, 1991; Strausfeld et al., 1991; Forsburg and Nurse, 1991). Some 100 oncogenes and several tumor suppressor genes have thus far been identified; specific functions are known for only a few.

The growth control circuit can also be altered without permanent genetic change by, for example, affecting the responsiveness of signal receptors, the concentration of signals, or the level of gene transcription (Holliday, 1991; Cross and Dexter, 1991; Lewin, 1991). These can come about through mimicry or inhibition of a signal or through physiological changes such as alteration of hormone levels that influence cell growth generally in some tissues.

Current reasoning holds that cell proliferation which results from changes at the levels of DNA sequence or DNA transcription, from changes at the level of growth control signal transduction, or from cell replication to compensate for toxic injury to tissue can begin a process of neoplastic change by increasing the number of cells that are susceptible to further events that may lead to uncontrolled growth. Such further events may include, for instance, errors in DNA replication that occur normally at a low background rate or effects of exposure to

2The term "mutations" includes the following permanent structural changes to DNA: single base-pair changes, deletions, insertions, transversions, translocations, amplifications, and duplications.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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mutagenic agents. Effects on elements of the growth control circuit, both permanent and transient, probably occur continuously in virtually all animals due to endogenous causes. Exogenous agents (e.g., radiation, chemicals, viruses) also are known to influence this process in a variety of ways.

Endogenous events and exogenous causes such as chemical exposure appear to increase the probability of occurrence of cancer by increasing the probability of occurrence of effects on one or more parts of the growth control circuit. The specific effect of one exogenous chemical, aflatoxin B1, on a tumor suppressor gene has been postulated on the basis of molecular epidemiology. Mutations in the tumor suppressor gene p53 are commonly found in the more prevalent human cancers, e.g., colon carcinomas, lung cancer, brain and breast tumors (Levine et al., 1991; Malkin et al., 1990). Populations with high exposure to aflatoxin B1 have a high incidence of hepatocellular carcinoma showing a base change at a specific codon in the p53 gene (Hollstein et al., 1991). However, the patterns of base changes in this gene that are found in virus-associated hepatocellular carcinomas and at other sites of sporadic tumors showing p53 gene mutation are different from the pattern found in aflatoxin B1-exposed populations, supporting the postulate that the specific codon change is a marker of the effect of aflatoxin B1 (Hayward et al., 1991).

Research continues to reveal more and more details about the cell growth cycle and to shed light on the events in carcinogenesis at the molecular level. As molecular biology research progresses, it will become possible to better understand the potential mechanisms of action of environmental carcinogens. It has long been known that many agents that are carcinogenic are also mutagenic. Recognition of the role of oncogenes and mutations of tumor suppressor genes has provided specific ideas about the linkage of chemical mutagenesis to the cell growth cycle. Other agents that are not mutagenic, such as hormones and other chemicals that are stimulants to cell replication (mitogens), can be postulated to play their role by acting directly on signal pathways, for example as growth signals or by disrupting signal transduction (Raff, 1992; McCormick and Campisi, 1991; Schuller, 1991).

While much has been revealed about likely mechanisms of action at the molecular level, much remains to be understood about tumorigenesis. A cell that has been transformed, acquiring the potential to establish a line of cells that grow to a tumor, will probably realize that potential only rarely. The process of tumorigenesis in animals and humans is a multistep one (Bouk, 1990; Fearon and Vogelstein, 1990; Hunter, 1991; Kumar et al., 1990; Sukumar, 1989; Sukumar, 1990), and normal physiological processes appear to be heavily arrayed against uncontrolled growth of a transformed cell (Weinberg, 1989). Powerful inhibition by signals from contact with neighboring normal cells is one known barrier (Zhang et al., 1992). Another is the immune system (at least for viral infection). How a cell with tumorigenic potential acquires additional properties that are necessary to enable it to overcome these and other inhibitory processes is

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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unknown. For known human carcinogens studied thus far, there is an often decades-long latency between exposure to carcinogenic agents and development of tumors, which may suggest a process of evolution (Fidler and Radinsky, 1990; Tanaka et al., 1991; Thompson et al., 1989).

The events in experimental tumorigenesis have been described as involving three stages: initiation, promotion, and progression. The initiation stage has been used to describe a point at which a cell has acquired tumorigenic potential. Promotion is a stage of further changes, including cell proliferation, and progression is the final stage of further events in the evolution of malignancy (Pitot and Dragan, 1991). The entire process involves a combination of endogenous and exogenous causes and influences. The individual human's susceptibility is likely to be determined by a combination of genetic factors and medical history (Harris, 1989; Nebreda et al., 1991), lifestyle, diet, and exposure to chemical and physical agents in the environment.

A number of key questions about carcinogenesis have no generic answers—questions such as: How many events are required? Is there a necessary sequence of events? The answers to these questions may vary for different tissues and species even though the nature of the overall process appears to be the same. The fact that the nature of the process appears empirically to be the same across species is the basis for using assumptions that come from general knowledge about the process to fill gaps in empirical data on a particular chemical. Knowledge of the mechanisms that may be operating in a particular case must be inferred from the whole of the data and from principles on which there is some consensus in the scientific community.

Information from studies that support inferences about mechanism of action can have several applications in risk assessment. For human studies, analysis of DNA lesions in tumor cells taken from humans, together with information about the lesions that a putative tumorigenic agent causes in experimental systems, can provide support for or contradict a causal inference about the agent and the human effect (Vahakangas et al., 1992; Hollstein et al., 1991; Hayward et al., 1991).

An agent that is observed to cause mutations experimentally may be inferred to have potential for carcinogenic activity (U.S. EPA, 1991a). If such an agent is shown to be carcinogenic in animals the inference that its mechanism of action is through mutagenicity is strong. A carcinogenic agent that is not mutagenic in experimental systems, but is mitogenic or affects hormonal levels or causes toxic injury followed by compensatory growth may be inferred to have effects on growth signal transduction or to have secondary carcinogenic effects. The strength of these inferences depends in each case on the nature and extent of all the available data.

These differing mechanisms of action at the molecular level have different dose-response implications for the activity of agents. The carcinogenic activity of a direct-acting mutagen should be a function of the probability of its reaching

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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and reacting with DNA. The activity of an agent that interferes at the level of signal pathways with many potential receptor targets should be a function of multiple reactions. The activity of an agent that acts by causing toxicity followed by compensatory growth should be a function of the toxicity.

1. Introduction

1.1. Purpose And Scope Of The Guidelines

The new guidelines will revise and replace EPA Guidelines for Carcinogen Risk Assessment published in 51 FR 33992, September 24, 1896. Through guidelines, EPA provides its staff and decisionmakers with guidance and perspectives necessary to their performing and using risk assessments. Publication of EPA's guidelines also provides basic information about the Agency's approaches to risk assessment for those who participate in Agency proceedings, or in basic research or scientific commentary on the subjects the guidelines cover.

As the National Research Council pointed out in 1983 that there are many questions encountered in the risk assessment process that are unanswerable based on scientific knowledge (NRC, 1983). To bridge the uncertainty that exists in areas where there is no scientific consensus, inferences must be made to ensure that progress continues in the assessment process. While the application of scientific inferences is both necessary and useful, the bases for these inferences must be continually reviewed to assure that they remain consistent with predominating scientific thought.

The guidelines incorporate basic principles and science policies based on evaluation of the currently available information. Certain general assumptions are described that are to be used when data are incomplete. Standard, default assumptions are described in order to maintain consistency and comparability from one assessment to the next. However, these guidelines explain that such assumptions are to be displaced by facts or better reasoning when appropriate data are available. Short of displacement, an analysis of any promising alternatives is expected to be presented alongside default assumptions.

These guidelines serve two policy goals that must be balanced: first, to maintain consistency of procedures that will support regularity in Agency decisionmaking and, second, to be adaptable to advances in science. Each risk assessment must balance these goals. To assist in balancing these and other science policies, the Agency will rely on input from the general scientific community through the Agency's established scientific peer review processes. The Agency will continually adapt its practices to new developments in the science of environmental carcinogenesis, and restate or revise, where appropriate, the principles, procedures, and operating assumptions of the risk assessment process. Changes will be made through either revisions to these guidelines or, more

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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frequently, issuance of documents on scientific perspectives and procedures and science policies that are developed under the aegis of the EPA Risk Assessment Forum.

1.2. Types Of Data Used In Carcinogenicity Assessment

Under these guidelines all available direct and indirect evidence is considered to assess whether the weight of the combined evidence supports a conclusion about potential human carcinogenicity. Direct evidence for carcinogenicity in humans comes from epidemiological studies of cancer or, in a few instances, from case reports. Other data providing direct evidence can come from long-term animal cancer bioassays. Indirect evidence comes from a variety of information about toxicological and biochemical effects related to carcinogenicity.

The most direct evidence for identifying and characterizing an agent's human cancer hazard potential is from human epidemiologic studies in which cancer is attributed to exposure to a specific agent. These studies are rarely available because the identification and follow up of populations of sufficient size and sufficient exposure to detect underlying risk is rarely feasible. Moreover, exposure to many potential but unidentifiable causative factors is frequent, making statistical attribution of incidence of a cancer to a single agent difficult. Much of the human evidence comes from occupational studies in which workplace exposure to an agent has been high, and the increased incidence of a cancer attributed to the agent has been distinguishable from other potential causes. Studies that are statistically not powerful enough to discern as association between environmental exposure and tumor incidence or to distinguish among potential causative factors are unable to show that an agent is not carcinogenic. Such studies, if well conducted, may nevertheless be used to estimate a "ceiling" on an agent's carcinogenic potency.

Long-term animal cancer bioassays are more frequently available for more agents than are epidemiologic studies. Approximately 400 of these have been conducted by the National Cancer Institute and National Toxicology Program (NTP)(Huff et al., 1988; NTP, 1992) and many additional ones have been conducted by others. The correspondence between positive results in human studies and long-term animal cancer bioassays is high (Tomatis et al., 1989; Rall, 1991) in the limited number of cases in which comparison is possible. In the absence of epidemiologic information, tumor induction in animal assays remains the best single piece of direct evidence on which to evaluate potential human carcinogenic hazard (OSTP, 1985). Results of animal studies have to be carefully analyzed along with other relevant data (such as metabolism and pharmacokinetic data used to compare animals and humans) to evaluate biological significance, causation, and reproducibility of results, and to determine the reasonable inferences about human hazard they support (Allen et al., 1988; Ames and Gold, 1990).

Data on physicochemical characteristics and biological effects of an agent

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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that make it more or less likely to affect processes involved in producing neoplasia provide important evidence supporting influences about carcinogenic potential. These include, for example, the ability to alter genetic information, influences on cell growth, differentiation, and death, and structural and functional analogies to other compounds that are carcinogenic.

1.3. Organization Of The Guidelines

These guidelines follow and should be read with two other publications that provide basic information and general principles. These are: Office of Science and Technology Policy (OSTP, 1985) Chemical Carcinogens: A Review of the Science and its Associated Principles (50 FR 10371), and National Research Council (NRC, 1983), Risk Assessment in the Federal Government: Managing the Process (Washington, DC, National Academy Press). The 1983 NRC document provided the 1986 guidelines with a thematic organization of risk assessment into hazard identification, dose-response assessment, exposure assessment, and risk characterization. This thematic organization has been slightly revised in these guidelines to focus attention on the importance of characterization in each part of the assessment. Nonetheless, the four questions addressed in these four areas remain the same; they are: Can the agent present a carcinogenic hazard to humans? At what levels of exposure? What are the conditions of human exposure? What is the overall character of the risk, and how well do data support conclusions about the nature and extent of the risk?

1.4. Application Of The Guidelines

The guidelines are to be used within the policy framework already provided by applicable EPA statutes and do not alter such policies. The Guidelines provide general directions for analyzing and organizing available data. They do not imply that one kind of data or another is prerequisite for regulatory action to control, prohibit, or allow the use of a carcinogen.

Regulatory decision making involves two components: risk assessment and risk management. Risk assessment defines the adverse health consequences of exposure to toxic agents. The risk assessments will be carried out independently from considerations of the consequences of regulatory action. Risk management combines the risk assessment with directives of regulatory legislation, together with socioeconomic, technical, political, and other considerations, to reach a decision as to whether or how much to control future exposure to the suspected toxic agents.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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2. Hazard Assessment

2.1. Introduction

Hazard assessment covers a wide variety of data relevant to the question, can an agent pose a human carcinogenic hazard? Available data may include: long term animal cancer bioassays and human studies, physical-chemical properties of the agent and its structural relationship to other carcinogens, studies of cellular and molecular interactions and mechanisms of action, and results from toxicological tests and experiments on the bioavailability and transformation of an agent in experimental animals and humans. Hazard assessment results are summarized in a hazard characterization that conveys the nature and impact of available data and appropriate scientific inferences about human carcinogenic hazard.

Experience shows that the nature and extent of information available on each agent is different and can vary from a wealth of epidemiologic data to only physical-chemical properties. Frequently, results from a long-term animal carcinogenesis bioassay are the only direct evidence available for the evaluation. These guidelines follow the assumption that chemicals with evidence to demonstrate carcinogenicity in animal studies are likely to present a carcinogenic hazard to humans under some conditions of exposure (OSTP, 1985). At the same time, there may be mechanistic, physiological, biochemical, or route-of-entry differences which alter the toxicological consequences in humans from those observed in the particular animals tested. When the results of animal testing are extrapolated to humans, effects observed at high continuous exposures are often projected to low or intermittent exposures and results from one route of exposure are often extrapolated to other routes of exposure. The risk analysis must examine each assumption and extrapolation for mechanistic and biological plausibility. The elements of hazard assessment described below are the foundation for these examinations.

The characterization of an agent's carcinogenic human hazard potential depends on the weight of all the relevant evidence. Studies are evaluated according to accepted criteria for study quality, sensitivity, and specificity. These have been described in several publications (Interagency Regulatory Liaison Group, 1979; OSTP, 1985; Peto et al., 1980; Mantel, 1980; Mantel and Haenszel, 1959; Interdisciplinary Panel on Carcinogenicity, 1984; National Center for Toxicological Research, 1981; National Toxicology Program, 1984; U.S. EPA, 1983a, b, c; Haseman, 1984). The hazard characterization describes how likely the agent is to be carcinogenic to humans, including the judgment whether or not the hazard is considered to be contingent on certain conditions of exposure (e.g., oral versus dermal exposure). The characterization summarizes the basis of, and confidence in, inferences drawn from data and the rationale for conclusions about

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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weight-of-evidence; these are accompanied by judgments on issues and uncertainties that cannot be resolved with available information.

The characterization of potential hazard is qualitative. It does not address the magnitude or extent of effects under actual exposure conditions. However, observations and conclusions from the hazard characterization that are relevant to quantitative dose-response analysis are carried forward to the section on quantitative dose-response analysis, and those that are relevant to actual exposure conditions are discussed in the risk characterization.

2.2. Integrating Data For Hazard Assessment

The assessment of potential carcinogenic hazard to humans is a process in which many kinds of data are integrated to examine the inferences and conclusions they support. The process is conducted as an interdisciplinary effort.

While the discussion that follows explores data analyses along separate disciplinary lines and provides for making intermediate summaries of human observational data and experimental data, it must be recognized that this is done simply for convenience of organization and marshalling of thought, and the individual analyses are interdependent not separate. Each kind of analysis, from evaluation of human studies to structure-activity relationship analysis, looks to the others for interpretive alliance and perspective. Confidence in conclusions is built upon the overall coherence of inferences from different kinds of data as well as confidence in individual data sets.

For example, in examining the issue of causation as part of human studies analyses, one uses knowledge of the biological activity of the agent in animal systems and of pertinent features of its structure, metabolism and other properties to address issues of biological plausibility of a causal hypothesis. Likewise, where there are no epidemiologic studies and one is examining relevance of animal responses to human hazard potential, one uses human data to address comparative biology of animals and humans with respect to, for instance, metabolism, pharmacokinetics, physiology, and disease history.

2.3. Analysis Of Human Data
2.3.1. Epidemiologic Studies

Epidemiology is the study of the distribution of a disease in a human population and the determinants that may influence disease occurrences. Epidemiologic studies provide direct information about the response of humans who have been exposed to suspect carcinogens and avoids the need for interspecies extrapolation of animal toxicological data.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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2.3.1.1. Exposure Focus

An identification of hazard in a human population depends critically on the exposure assessment, which consists of two components: (a) the qualitative determination of the presence of an agent in the environment and (b) the quantitative assessment. An exposure assessment which includes an attribution of quantified exposure to an individual is considered more precise and will carry more weight in an evaluation of human hazard. In many epidemiologic studies, the populations are selected and studied retrospectively, and the time between exposure and observation of effects is very long because of the latency of cancer. The past exposure is a critical determinant. In an environmental situation, quantitative exposure assessment is usually difficult to achieve due to lack of measures of past exposure. This is one reason why occupational studies where exposure is based on job classification are often used for identifying environmental hazard. Past occupational exposures are usually considered to be at higher levels than those encountered environmentally; therefore, the question whether any identified hazard is pertinent at lower exposure levels needs to be addressed.

Exposure assessment becomes more complicated when the exposure is to a complex mixture of incompletely identified chemicals. In addition, human exposures to agents can occur by more than one route as compared to the controlled exposure regimens used in the animal carcinogenicity studies (e.g., occupational exposure to solvents can occur through inhalation and dermal absorption). The characterization of the patterns of exposure to identify exposure-effect relationships is another consideration. Important exposure measurements in epidemiologic studies include cumulative exposure (sometimes time-weighted), duration of exposure, peak exposure, exposure frequency or intensity, and ''dose" rate. Some insight on which measurement of exposure will be the best predictor of a cancer can come from an understanding of the disease process itself.

In epidemiological studies, "biological markers," usually the reaction products of an agent or its metabolite with DNA or a protein or other markers of exposure such as excretion of metabolites in urine have been increasingly considered as reliable measures of exposure. More rarely a marker of effect specific to an agent may be found (Vahakangas et al., 1992). Information on the relationship between exposure or effect and markers is often derived from metabolism and kinetic studies in animals. Validation of the relationship with comparative human data is needed to support confidence in use of such markers.

{The generic issue of use biomarker of exposure and effect is still under consideration.}

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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2.3.1.2. Types of Epidemiology Studies

Various types of epidemiologic studies or reports can provide useful information for identifying hazards. An important consideration is the validity and representativeness of the studied population with respect to the larger population of interest. Study designs include cohort, case-control, proportionate ratio, clinical trials, and correlational studies. In addition, cluster investigations and case reports, while not constituting studies, may yield useful information under certain situations (e.g., reports associated with exposure to vinyl chloride and diethylstilbestrol). The above designs have well-defined strengths and limitations (Breslow et al., 1980; 1987; Kelsey et al., 1986; Lilienfeld and Lilienfeld, 1979; Mausner and Kramer., 1985; Rothman, 1986).

2.3.2. Elements of Critical Analysis

Aspects of the available human data, which are described in this section, are evaluated to determine whether there is a causal relationship between exposure to the agent and an increase in cancer incidence. Certain elements of analysis are brought to bear on the criteria for causality, which are listed and discussed in Section 2.3.2.5. In general, these elements address the study design and conduct; the ability to sort out the potential role of the agent in question as opposed to other risk factors; assessment of exposure of the study and referent populations to the agent and to other risk factors; and, given all of the above, the statistical power of the study or studies.

2.3.2.1. Exposure

Exposure is the foundation upon which any exposure-effect relationship is evaluated. Often, the exposure is not to a single agent, but to a combination of agents (e.g., exposure to chloromethylmethyl ether and its ever-present contaminant bischloromethyl ether). When exposures occur simultaneously, it is generally assumed that each chemical exposure contributes to the exposure- or exposures-effect relationship.

Exposure can be defined in hierarchical levels. Greater weight will be given to studies where exposures are more precisely defined and can be quantified. The broadest definition of exposure is that inferred for a group of individuals living in a geographic area. At this level, it is not known whether all individuals are exposed to the agent, and if exposed, the patterns and lengths of exposure. The result is a mixture of individuals with higher exposure and those with little or no exposure. This leads to exposure misclassification, which, if random, may result in a study's reduced ability to detect underlying elevations in risk. For the same reasons, exposure as defined by assignment to a broad occupational cate-

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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gory in the absence of qualitative or quantitative data yields less useful information on an individual's exposure.

A more recent application in epidemiologic studies is the use of job-exposure matrices to infer semi-quantitative and quantitative levels of exposure to specific agents (Stewart and Herrick, 1991). The job-exposure matrix has been applied to occupational scenarios where at least some current and historical monitoring data exist. In examining exposure levels inferred from a job-exposure matrix, the basis of the monitoring data must be considered—whether data are from routine monitoring or reflect accidental (i.e., higher than average) releases.

Biological markers are indicators of processing within a biological system. Using such a marker as a measure of exposure is potentially the most reliable level of data since the quantity measured is thought to more precisely characterize a biologically available dose, rather than exposure that is the amount of material presented to the individual and is usually inferred from a measurement of atmospheric concentrations (NAS, 1989). Validated markers are the most desirable, i.e., markers which are highly specific to the exposure and those which are highly predictive of disease (Blancato, OHR Biomarker Strategy, cite published paper; Hulka and Margolin, 1992) (e.g., urinary arsenic (Entertine et al., 1987), and alkylated hemoglobin (hemoglobin adducts) from exposure to ethylene oxide (Callemen et al., 1986; van Sittert et al., 1985).

2.3.2.2. Population Selection Criteria

The study population and the comparison or referent population are identified and examined to decide whether or not comparisons between populations are appropriate and to determine the extent of any bias resulting from their selection. The ideal referent population would be similar to the study population in all respects except exposure to the agent in question. Potential biases (e.g., healthy worker effect, recall bias, selection bias, and diagnostic bias) and the representativeness of the studied population for a much larger population are addressed.

Generally, the referent population in cohort studies consists of mortality or incidence rates of a larger population (e.g., the U.S. population). The healthy worker bias is specific to occupational cohort studies, and it asserts that an employed population is healthier than the general population (McMichael, 1976). The influence of the healthy worker effect is toward a more favorable mortality in the exposed population; this influence is thought to decrease with increasing age and to have less influence on site-specific cancer rates. The influence of the healthy worker effect is thought to be minimized by the use of an internal comparison group (e.g., incidence or mortality rates of employees who are from the same company, but not among the employees in the study population).

In case-control designs, the potential for differences in recalling past events (recall bias) between the case and control series needs to be evaluated. The

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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characteristics of the control series also need to be discussed. Hospital controls have associated limitations with respect to possible associations with the exposure of interest. Randomly-selected population or community controls are thought to be more like cases in the case series; however, response rates are often lower.

2.3.2.3. Confounding Factors

A confounding variable is a risk factor for the disease under study that is distributed unequally among the exposed and unexposed populations. Adjustment for possibly confounding factors can occur either in the design of the study (e.g., matching on critical factors) or in the statistical analysis of the results. If adjustment within the study data is not possible due to the presentation of the data or because needed information was not collected during the study, indirect comparisons may be made (e.g., in the absence of direct smoking data from the study population, an examination of the possible contribution of cigarette smoking to increased lung cancer risk and to the exposure in question may include information from other sources such as the American Cancer Society's longitudinal studies (Hammond, 1966; Garfinkel and Silverburg, 1991).

In a collection of heterogenous studies possible confounding factors are usually randomly distributed across studies. If consistent increases in cancer risk are observed across the collection of studies, greater weight is given to the agent under investigation as the etiologic factor even though the individual studies may not have completely adjusted for confounding factor.

2.3.2.4. Sensitivity

Epidemiologic studies which consist of a large number of individuals with sufficient exposure to a putative cancer-causing agent and adequate length of time for cancer development or detection are considered to have a greater ability to detect cancer risk. Studies for review, however, do not always fulfill these criteria. In addition, the ability to detect increases in relative risk associated with environmental exposure is very difficult due to heterogeneous exposure regarding both pattern and levels and which potentially bias risk toward the null hypothesis of no effect.

If the underlying risk is actually increased, examination of persons considered at higher risk increases the detection ability of a study. Such examination may include an evaluation of risk among individuals with higher or peak exposure, with greater duration of exposure, or with the longest time since first exposure (to allow for latency of effect), and those of older age, and those with long latencies.

A study in which no increases in risk were observed may be useful for inferring an upper limit on possible human risk. Statistical reanalysis is another

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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approach for examining the sensitivity of results from an individual study (e.g., the dose-response relationship reported in one formaldehyde-exposed cohort (Blair et al., 1986) has been examined by several investigators (Blair et al., 1987; Sterling and Weinkam, 1987; Collins et al., 1988; Marsh, 1992). These further analyses are a reaggregation of exposure groups or an examination of the influence of a subgroup on the disease incidence of the much larger group.

Statistical methods for examining several studies together are frequently applied to the collection of data. These methods, commonly referred to as meta-analysis, are used to contrast and combine results of different studies with the goal of increasing sensitivity. In meta-analysis, study results are evaluated as whether they differ randomly from the null hypothesis of no effect (Mann, 1990); meta-analysis presumes that observed results are not biased. If an underlying effect is not present, the observed results should appear randomly distributed and cancel each other when studies are combined (Mann, 1990). Several important issues are pertinent to meta-analysis. These are controlling for bias and confounding prior to combining studies, criteria for study inclusion, assignment of weights to individual studies, and possible publication and aggregation bias. Greenland, 1987 discusses may of these issues in addition to identifying methodologic approaches.

{Participants at the December 4, 1992, Society for Risk Analysis on cancer risk assessment issues were asked to look at meta-analysis.}

2.3.2.5. Criteria for Causality

A causal interpretation is enhanced for studies to the extent that they meet the criteria described below. None of the criteria, with the exception of a temporal relationship, should be considered as either necessary or sufficient in itself to establish causality. These criteria are modelled after those developed by Hill in the examination of cigarette smoking and lung cancer (Rothman, 1986).

a.

Temporal relationship: This is the single absolute requirement, which itself does not prove causality, but which must be present if causality is to be considered. The disease occurs within a biologically reasonable time frame after the initial exposure. The initial period of exposure to the agent is the accepted starting point in most epidemiologic studies.

b.

Consistency: Associations are observed in several independent studies of a similar exposure in different populations. This criterion also applies if the association occurs consistently for different subgroups in the same study.

c.

Magnitude of the association: A causal relationship is more credible when the risk estimate is large and precise (narrow confidence intervals).

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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d.

Biological gradient: The risk ratio is correlated positively with increasing exposure or dose. A strong dose-response relationship across several categories of exposure, latency, and duration is supportive although not conclusive for causality given that confounding is unlikely to be correlated with exposure. The absence of a dose-response relationship, however, should not be construed by itself as evidence of a lack of a causal relationship.

e.

Specificity of the association: The likelihood of a causal interpretation is increased if a single exposure produces a unique effect (one or more cancers also found in other studies) or if a given effect has a unique exposure.

f.

Biological plausibility: The association makes sense in terms of biological knowledge. Information from animal toxicology, pharmacokinetics, structure-activity relationship analysis and short-term studies of the agent's influence on events in the carcinogenic process are considered.

g.

Coherence: The cause-and-effect interpretation is in logical agreement with what is known about the natural history and biology of the disease, i.e., the entire body of knowledge about the agent.

2.4 Summary Of Human Evidence

{The process in combining all findings relevant to human carcinogenic potential is an issue for further development. The need for this summarization step for human evidence and the one in Section 2.5 for experimental evidence are open questions at EPA.}

Each epidemiological study is critically evaluated for its relevance with respect to the exposure-effect relationship, exposure assessment such as intensity, duration, time since first exposure, and methodological issues such as study design, selection and characterization of comparison group, sample size, handling of latency, confounders, and bias.

Following critical evaluation, the totality of the weight-of-evidence for human carcinogenicity is assessed and summarized according to one of the following four categories, which are meant to represent a judgment regarding the weight of all of the human evidence even if only one study exists on the subject. Rarely, the judgment can be based on a series of case reports. More likely, the evaluation will involve several studies. Inferences from summary analyses such as meta-analysis can provide support for placement into these categories. In addition, evidence that the agent in question is metabolized to a compound, for which independent human evidence exists, is supportive of the categorization.

The weight a particular study or analysis is given in the evaluation depends on its design, conduct, and avoidance of bias (selection, confounding, and mea-

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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surement) (OSTP, 1984). Results, both positive and null, are considered in light of the study's rigor. The weight of evidence is based on the plausibility of the association and the conclusiveness of observed findings. Greater plausibility and conclusiveness can be ascribed to an exposure-effect relationship when it can be explained in terms of adherence to the criteria for causality, including coherence with other evidence such as animal toxicology. The plausibility of exposure-effect relationship also can be bolstered or mitigated by evidence of structure-activity relationship analysis with well characterized agents, studies of mechanism of action, understanding of metabolic pathways, and other indirect evidence relevant to human effects. A mixture (e.g., cigarette smoke, coke oven emissions) may be categorized as an agent when causation is ascribed to the mixture, but not to necessarily to its individual components.

2.4.1. Category 1

Plausible evidence exists, and from this evidence a conclusive causal association can be judged. Cause and effect relationships are supported with results from well-designed and conducted studies in which random or nonrandom error can be reasonably excluded.

2.4.2. Category 2

Evidence exists to suggest that causal association is plausible; however, such evidence is not conclusive due to a number of reasons which may include lack of consistency, wide confidence intervals which may or may not include a risk, or absence of an observed dose-response relationship. The effect of random or nonrandom error in individual studies which could influence the risk ratio away from the null is considered minimal. This category covers a broad range of possible weights of evidence. At the top of the category are highly suggestive, but short of convincing data. At the bottom of the category are suggestive but weak data. A statement of the relative position of data in this continuum accompanies the description of the data as Category 2.

2.4.3. Category 3

The body of evidence is inconclusive. The assertion of a causal association is not plausible from the available data in which studies of equal quality have contradictory results in which random or nonrandom error is a more likely explanation for observations of increased risk. This category also applies when no epidemiologic data are available.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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2.4.4. Category 4

The available studies are designed with defined ability to detect increases in risk, and resultant risk ratios are precise with tight confidence intervals. Evidence derived from the studies consistently show no positive association between the suspect agent and cancer. The evidence is described as showing no cause and effect relationship at the exposure levels studied. It is not considered to show that the agent is non-carcinogenic under all circumstance unless the evidence is so complete that potential for human carcinogenicity can be eliminated.

2.5. Analysis Of Long-Term Animal Studies

Long-term animal studies are evaluated to decide whether biologically significant responses have occurred and whether responses are statistically significantly increased in treated versus control animals. The unit of comparison is an experiment of one sex, in one species.

2.5.1. Significance of Response

Evidence for carcinogenicity is based on the observation of biologically and statistically significant tumor responses in specific organs or tissues. Criteria for categorizing the strength of evidence of animal carcinogenicity in bioassays have been established by the National Toxicology Program (NTP, 1987). Animal study results are evaluated for adequacy of design and conduct (40 CFR Part 798). The results are described and biological significance of observed toxicity is evaluated (non-neoplastic endpoints included).

{For EPA's purposes, the criteria for evaluating animal cancer bioassays are still under review, and could be somewhat different from those of NTP. Nevertheless, much of the animal cancer data available to EPA carries the NTP designations of "clear, some, equivocal, or none".}

Interpretation of animal studies is aided by the review of target organ toxicity and other non-neoplastic effects (e.g., changes in the immune and endocrine systems) that may be noted in prechronic or other toxicological studies. Time and dose-related changes in the incidence of preneoplastic and neoplastic lesions may also be helpful in interpreting responses in long-term animal studies.

It is recognized that chemicals that induce benign tumors also frequently induce malignant tumors, and that certain benign tumors may progress to malignant tumors. Benign and malignant tumor incidence are combined for analysis of carcinogenic hazard when scientifically defensible (OSTP, 1985; Principle 8).

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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The Agency follows the National Toxicology Program framework for combining benign and malignant tumor incidence of a particular site (McConnell, 1986).

Elevated tumor incidences in adequate experiments are analyzed for biological and statistical significance. Generally, a statistical test that shows a positive trend in dose-response at a level of significance of five percent (i.e., the likelihood of false positive results is less than five percent) supports a conclusion that the experiment is positive. If false positive outcomes are a serious concern, the use of a formal multiple comparison adjustment procedure should be considered. No rigid decision rule should be used as substitute for scientific judgment. Other statistical tests may be applied if the trend test is not statistically significant or, for some reason, not applicable for a given experiment. The significance level should be adjusted if multiple comparisons of the same data are made, in order to avoid raising the overall likelihood of false positives (Haseman, 1983, 1990; U.S. FDA, 1987).

Data from all long-term animal studies, positive and negative, are to be considered in the evaluation of carcinogenicity. Different results according to species, sex, or strain, or by route of administration, duration of study or site of effect are not unexpected. The issues are how different results affect the weight of evidence and whether the differences suggest the operation of any particular mechanisms of action or tissue sensitivity that may assist in judging human relevance.

2.5.2. Historical Control Data

{NOTE TO THE READER: The issues of how to consider historical control data and high background tumors are knotty ones. For high background tumors there are varying views, some question relevance, but usually there are insufficient data about the mechanism of action to question its relevance. Others point to the fact that both humans and animals have tissues with high background rates.}

Historical control data often add valuable perspective in the evaluation of carcinogenic responses (Haseman et al., 1984). For the evaluation of rare tumors, even small increases in tumor response over that of the concurrent controls may be significant compared to historical data. Historical data can also identify sites with high spontaneous background in the test strain. Nevertheless, historical control data have limitations as compared to concurrent control data. One limitation is the potential for genetic drift in laboratory strains over time that makes historical data less useful beyond a few years. Other limitations are the differences in pathological examinations at different times and in different laboratories; these are due to changes over time in criteria for evaluating lesions and to variations in preparation techniques and reading of tissue samples between laboratories. Other differences may include biological and health differences in

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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animal strains from different suppliers. Concurrent controls are, for these reasons, more valuable comparison for judging whether observed effects in dosed animals are treatment related.

Comparison of an observed response that appears to be treatment related with historical control data may call the response into question if the observed response is well within the range of historical control data. Whenever historical control data are compared with the current data the reasons should be given for judging the historical control data to be adequately representative of the current expected response background.

2.5.3. High Background Tumor Incidence

Tumor data at sites with high spontaneous background requires special consideration (OSTP, 1985; Principle 9). Questions raised about high background tumors in animals (and humans) are whether they are due to particular genetic predispositions or ongoing proliferative processes that are species-specific prerequisites to a neoplastic response or, on the other hand, represent sensitivities due to biological processes that are alike among species. Answering these questions requires a body of research data beyond the data obtained in standard animal studies. Unless there are research data to establish that such tumor data at a site occur because of a mechanism-of-action that is unique to the species, strain, and sex with the high background, the tumor data are considered, as are other tumor data, in the overall weight of evidence. These data may receive relatively less weight than other tumor data.

2.5.4. Dose Issues

Long-term animal studies at or near the maximum tolerated dose level (MTD) are used to ensure an adequate power for the detection of carcinogenic activity of an agent (NTP, 1984; IARC, 1982). The MTD is a dose which is estimated to produce some minimal toxic effects in a long term study (e.g., a small reduction in body weight), but should not shorten an animal's life span or unduly compromise normal well-being except for chemically induced carcinogenicity (International Life Sciences Institute, 1984; Haseman, 1985). Assays in which the MTD may have been exceeded or may not have been reached require special scrutiny.

Exceedance of the MTD in a study may result in tumorigenesis that is secondary to tissue damage or physiological damage and is more a function of this damage than of the carcinogenic influence of the particular agent tested. Inferences drawn from the study must consider observed non-neoplastic toxicity and the tissues affected, as well as the existence of carcinogenic effects in tissues, or at doses, not affected by the exceedance. Study results at doses that exceed the

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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MTD can be rejected if toxic damage is so severe as to compromise interpretation.

Null results in long-term animal studies at exposure levels above the MTD may not be acceptable if animal survival is so impaired that the sensitivity of the study is significantly reduced below that of a conventional chronic animal study at the MTD. The import of non-positive studies at exposure levels below the MTD may be compromised by lack of power to detect effects.

2.5.5. Human Relevance

Relevance of tumor responses to human hazard is a judgment that is integral to analysis of bioassay results. The assumption is made under these guidelines that observation of tumors at any animal tissue site supports an inference that humans may respond at some site. This assumption is reexamined as data on the issue become available for specific responses. The Agency will undertake analyses of relevance issues as needed in reports to be published from time to time (e.g., USEPA, 1991b).

If information on the mechanism of tumorigenesis supports the conclusion that a response seen in an animal study is unique to that species or strain, the response is considered to provide no evidence for human hazard potential (U.S. EPA, 1991a). Agency decisions of this kind about particular animal responses are made and published under the aegis of the EPA Risk Assessment Forum. Such mechanistic uniqueness is be differentiated from quantitative differences in dose-response which are not, per se, issues of relevance.

2.6. Analysis Of Evidence Relevant To Carcinogenicity

Certain structural, chemical, and biological attributes of an agent provide key information about its potential to cause or influence carcinogenic events. These attributes and comparative studies between species provide information to support carcinogenic hazard identification and compare potential activity across species. The following sections provide guidance for inclusion of analyses of these kinds of evidence in hazard identification.

2.6.1. Physical-Chemical Properties

Physical-chemical properties that can affect the agent's absorption, tissue distribution (bioavailability), biotransformation, or chemical degradation in the body are analyzed as part of the overall weight of evidence on hazard potential. These include, but are not limited to: molecular weight, size, and shape; physical state (gas, liquid, solid); water or lipid solubility that can influence retention and tissue distribution; and potential for chemical degradation or stabilization in the body.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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Interaction with cellular components and reactivity with macromolecules is a second major area covered. Factors such as molecular size and shape, electrophilicity, and charge distribution are analyzed to decide whether they would facilitate such reactions by the agent.

2.6.2. Structure-Activity Relationships

The role of structure-activity relationship (SAR) analysis in the assessment of the carcinogenic risk of an agent in question is dependent upon the availability and the quality of the toxicological data on the agent. For chemicals with data from reasonably conducted studies, SAR analysis is useful in providing input to determine the probable mechanism of action, which is important for hazard identification and for decisions on the appropriate methodology for quantitative risk assessment. For chemicals with either unsatisfactory or inadequate carcinogenicity data, SAR analysis may be used to generate, bolster, or mitigate the carcinogenic concern for the chemical, depending on the strength of and confidence in the SAR analysis. In addition, SAR analysis can also serve as a guide to evaluate carcinogenic potential of untested chemicals.

Currently, SAR analysis is most useful for chemicals that are believed to produce carcinogenesis, at least initially, through covalent interaction with DNA (i.e., DNA-reactive mutagenic electrophilic or proelectrophilic chemicals) (Ashby and Tennant, 1991; Woo and Arcos, 1989). In analyzing the SAR of DNA-reactive mutagenic chemicals, the following parameters should be considered (Woo and Arcos, 1989):

a.

the nature and reactivity of the electrophilic moiety or moieties present;

b.

the potential to form electrophilic reactive intermediate(s) through chemical, photochemical; or metabolic activation;

c.

the contribution of the carrier molecule to which the electrophilic moiety(ies) is attached;

d.

physicochemical properties (e.g., physical state, solubility, octanol-water partition coefficient, half-life in aqueous solution);

e.

structural and substructural features (e.g., electronic, stearic, molecular geometric);

f.

metabolic pattern (e.g., metabolic pathways and activation and detoxification ratio); and

g.

the possible exposure route(s) of the subject chemical.

Following compliation of a carcinogenicity database for structural analogs, the above parameters are used to compare and place the subject chemical as to its carcinogenic potential among its analogs or congeners. In addition, the analysis is supplemented with any available information on the pertinent toxic effects of the compound, its potential metabolites, and its structural analogs. The

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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pertinent toxic effects are those known to contribute to carcinogenesis such as immune suppression or mutagenicity.

Suitable SAR analysis of non-DNA-reactive chemicals and of DNA-reactive chemicals that do not appear to bind covalently to DNA requires knowledge or postulation of the most probable causative mechanism(s) of action (e.g., receptor-mediated, cytotoxicity related) of closely related carcinogenic structural analogs. Examination of the physicochemical and biochemical properties of the subject chemical may then allow one to assess the likelihood that such a mechanism also may be applicable to the chemical in question and to determine the feasibility of conducting SAR analysis based on the mechanism.

2.6.3. Metabolism and Pharmacokinetics

Studies of the absorption, distribution, biotransformation and excretion of agents are used to make comparisons among species to assist in determining the implications of animal responses for human hazard assessment, to support identification of toxicologically active metabolites, to identify changes in distribution and metabolic pathway or pathways over a dose range and between species, and to make comparisons among different routes of exposure.

In the absence of data to compare species, it is necessary to assume that pharmacokinetic and metabolic processes are qualitatively comparable. If data are available (e.g., blood/tissue partition coefficients and pertinent physiological parameters of the species of interest), physiologically based pharmacokinetic models can be constructed to assist in determination of tissue dosimetry, species-to-species extrapolation of dose, and route-to-route extrapolation (Connolly and Andersen, 1991).

Analyses of adequate metabolism and pharmacokinetic data can be applied toward the following as data permit. Confidence in conclusions is greatest when in vivo data are available.

a.

Identifying metabolites and reactive intermediates of metabolism and determining whether one or more of these intermediates are likely to be responsible for the observed effects. This information on the reactive intermediates will support and appropriately focus SAR analysis, analysis of potential mechanisms of action, and, in conjunction with physiologically based pharmacokinetic models, estimation of tissue dose in risk assessment (D'Souza et al., 1987; Krewski el al., 1987).

b.

Identifying and comparing the relative activities of relevant metabolic pathways in animals with those in humans. This analysis can give insight on whether extrapolation of results of animal studies to humans will produce useful results.

c.

Describing anticipated distribution within the body, and possibly identifying target organs. Use of water solubility, molecular weight, and

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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structure analysis can support inferences about anticipated qualitative distribution and excretion. In addition, describing whether the agent or metabolite of concern will be excreted rapidly or slowly or will be stored in a particular tissue or tissues to be mobilized later can identify issues in comparing species and formulating dose-response assessment approaches.

d.

Identifying changes in pharmacokinetics and a metabolic pathway or pathways with increases in dose. These changes may result in the formation and accumulation of toxic products following saturation of detoxification enzymes. These studies have an important role in providing a rationale for dose selection in carcinogenicity studies. In addition, these studies may be important in estimating a dose over a range of high to low exposure for the purpose of dose-response assessment.

e.

Determining the bioavailability of different routes of entry by analyzing uptake processes under various exposure conditions. This analysis supports identification of hazard for untested routes of entry. In addition, use of physicochemical data (e.g., octanol-water partition coefficient information) can support an inference about the likelihood of dermal absorption (Flynn, 1990).

In all of the above-listed areas of inquiry, attempts are made to clarify and describe as much as possible the variability to be expected because of differences in species, sex, age, and route of entry. Utilization of pharmacokinetic information takes into account that there may be subpopulations of individuals who are particularly vulnerable to the effects of an agent because of metabolic deficits or pharmacokinetic or metabolic differences (genetically or environmentally determined) from the rest of the population.

2.6.4. Mechanistic Information

{The material in this section is only a start. Substance-specific risk assessments may have little or no data in this category. Even when data are available, there is no standard for what is acceptable or what to expect. If there are no data, we will have to use default assumptions. How much information is enough is difficult to say until testing in this area is more regular.}

''Knowledge of carcinogenic mechanisms is incomplete in all cases. Information on how particular agents are likely to cause cancer may, however, be useful for appreciating more accurately the hazard that such agents pose to humans" (IARC, 1991). Results from short-term toxicological tests and molecular and cellular mechanistic studies are also useful in the interpretation of epidemiological and rodent chronic bioassay data used in hazard identification and characterization. These data may provide guidance for dose-response modelling.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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Testing for tumorigenicity is usually done in long-term assays that involve exposure for much of an animal's lifespan.

Data from the long-term animal studies and the toxicity studies preceding them (e.g., evidence of lesion progression, or lack of progression, and hyperplasia at the same site as the neoplasia) may suggest a line of inquiry for further study. Cell necrosis is often an early finding (e.g., 20-90 days) and provides indirect evidence for subsequent tissue regeneration and compensatory growth mechanisms when these events are not directly observed. Other early changes observed during pre-chronic studies range from biochemical changes to altered hormone levels to organ enlargement (hyperplasia) to specific and marked histopathological changes (Hildebrand et al., 1991).

Conventional animal cancer bioassays provide little information on mechanism of action. Short-term animal assays generally have more defined study designs to provide information about potential mechanisms of action. A large number of short-term assays examine biological activities relevant to the carcinogenic process (e.g., mutagenesis, tumor promotion, aberrant intercellular communication, increased cell proliferation, malignant conversion, immunosuppression). In the future, mechanistic-based end points should play an increasing, and perhaps major, role in the assessment of cancer risk.

2.6.4.1. Genetic Toxicity Tests

Information on genetic damaging events induced by an agent is revealing about the possible mechanism of action of a carcinogen. Although the effectiveness of genetic toxicology tests in predicting cancer has been questioned (Brockman and DeMarini, 1988), the ability of these tests to detect mutagenic carcinogens has not been seriously challenged (Brockman and DeMarini, 1988; Prival and Dunkel, 1989; Tennant and Zeiger, 1992; Shelby et al., 1992; Jackson et al., 1992).

Recent studies on oncogenes provide evidence for the linkage between mutation and cancer (Bishop, 1991); activation of protooncogenes to oncogenes can be triggered, for example, by point mutations, DNA insertions, or chromosomal translocation (Bishop, 1991). In addition, the inactivation of tumor suppressor genes (anti-oncogenes) can occur by chromosomal deletion or aneuploidy (chromosome loss), and mitotic recombination (Bishop, 1989; Varmus, 1989; Stanbridge and Vavenee, 1989).

Genetic toxicology tests have been described in various reviews (Brusick, 1990; Hoffman, 1991). The EPA has published various testing requirements and guidelines for detection of mutagenicity (USEPA, 1991a). A useful method to "portray" data graphically, and which provides a reasonable starting point for analysis, is the genetic activity profile (GAP) methodology developed by the USEPA (Garrett et al., 1984; Waters et al., 1988).

Many test systems have been developed to assay agents for their mutagenic

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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potential.3 These include assays for changes in DNA base pairs of a gene (i.e., gene mutations) and microscopically visible changes in chromosome structure or number. Structural aberrations include deficiencies, duplications, insertions, inversions, and traslocation. Other assays that do not measure gene mutations or chromosomal aberrations per se provide some information on an agent's DNA damaging potential (e.g., tests for DNA adducts, strand breaks, repair, or recombination).

Distinguishing a carcinogenic agent as a mutagen or nonmutagen is an important decision point in defining the mechanism of action. To designate a putative carcinogen as a mutagen, there should be confidence that the primary target is DNA. Mutagenic end points that involve stable changes in DNA structure are emphasized because of their relevance to carcinogenesis. These include gene mutations and chromosomal aberrations.

To be of value in cancer risk assessment, genetic toxicology data must meet the demands of scientific scrutiny. A higher level of confidence that a carcinogen is a mutagen is assigned to agents that consistently induce direct structural changes in DNA in a number of test systems. Although important information can be gained from in vitro assays, a higher level of confidence is given to a data set that includes in vivo evidence. In vivo data is emphasized because many agents require metabolic conversion to an active intermediate for biological activity. Metabolic activation systems can be incorporated into in vitro assay; however, they do not always mimic mammalian metabolism perfectly. If available, human genetic toxicity end points relevant to carcinogenesis are important in vivo data.

It is not possible to illustrate all potential combinations of evidence, and considerable judgment must be exercised in reaching conclusion. Certain responses in tests that measure DNA damaging potential (e.g., DNA repair activity, adducts or strand breakage in DNA) other than gene mutations and chromosomal aberrations may provide a basis for raising the level of confidence in designating a carcinogen as mutagenic.

There are many other mechanisms by which agents cause genetic damage secondary to other effects. For example, an agent might interfere with DNA repair or possibly increase DNA damage through an increase in oxidative radical production (Cerutti et al., 1990). Reliance on evidence for induced gene mutations or chromosomal aberrations to define a mutagenic carcinogen is not meant to downplay the importance of these secondary mechanisms or other genetic end points.

Aneuploidy (i.e, a change in chromosome number) may play an important role in the development of some tumors (Kondo et al., 1984; Cavenee et al., 1983; Barrett et al., 1985), but it may result from interactions with cellular com-

3 Ability to induce heritable or stable alterations in DNA structure and content.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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ponents (e.g., mitotic apparatus) other than with DNA. For this reason, aneuploidy is not considered evidence for designating a carcinogen as mutagenic. Aneuploidy is important information regarding potential carcinogenicity by other genetic mechanisms and should be factored into the evaluation concerning mechanisms of action.

Because mutagenic carcinogens have been observed to induce tumors across species and at multiple sites, evidence of both mutagenicity and tumor responses in multiple species or sexes significantly increases concern for the human carcinogenic potential of an agent. Absence of mutagenicity in multiple test systems gives insight into alternative mechanisms by which non-mutagenic carcinogens may act. The consideration of alternative non-mutagenic mechanisms does not necessarily provide a basis for discounting positive results in the animal cancer bioassay and thus does not negate the concern for human risk. On the other hand, evidence for non-mutagenicity and the lack of responses in a chronic rodent bioassay increases the confidence that an agent is not a human hazard.

2.6.4.2. Other Short-Term Tests

In addition to genetic toxicity tests, information on increased cell proliferation, cell transformation, aberrant intercellular communication, receptor mediated effects, changes in gene transcription (i.e., events that involve a change in the function of the genome) can provide useful information in the evaluation of mechanism of action and insight into the carcinogenic potential of an agent. It is not possible to describe all the data that might be encountered in a substance-specific assessment. Thus, the most conventional ones or those that are currently emphasized are mentioned as examples.

Cell proliferation plays a key role at each stage in the carcinogenic process and it is well established that increased rates of cell proliferation are associated with increased cancer risk. This increased risk is due to the increased susceptibility of proliferating cells to both spontaneous genetic damage as well as that induced by mutagens. Therefore, mitogenic activity in a mutagenic agent could be expected to further increase the probability of mutagenesis and, therefore, carcinogenesis. Cell proliferation or mutation alone are insufficient to cause neoplasia; further events are required for cells to escape from growth control, to attain the ability to grow independently, and to acquire invasiveness.

Evidence for the increased rate of cell division may be determined by measuring the mitotic index, or by supplying a specific DNA precursor to the cell (e.g., 3H-thymidine or bromodeoxyuridine) and counting the percentage of cells that have incorporated the precursor into the replicating DNA, or by immunodetection of proliferation-specific antigens. These analyses are carried out in vitro, during pre-chronic studies, or as part of the long-term animal cancer bioassay.

Non-mutagenic carcinogens are more likely than mutagenic carcinogens to affect a specific sex or organ. Stable cell populations with a potential for a high

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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rate of cell replication are more often affected than cell populations with a naturally high rate of replication. These properties have been used to develop two stage initiation-promotion studies based on preneoplastic lesions or tumors of the mammary gland, urinary bladder, forestomach, thyroid, kidney, and liver. Such tests provide mechanistic insight as well as supportive evidence for carcinogenicity (Drinkwater, 1990).

Several short-term tests respond to both mutagenic and non-mutagenic carcinogens. Assays for measuring perturbation of gap-junctional intercellular communication may provide and indication of carcinogenicity, especially promotional activity, and provide mechanistic information (Yamasaki, 1990). Cell transformation assays have been widely used for studying mechanistic aspects of chemical carcinogenesis because in vitro cell transformation is considered to be relevant to the in vivo carcinogenic process.

2.6.4.3. Short-Term Assays for Carcinogenesis

In addition to more conventional long-term animal studies, other shorter-term animal models can yield useful information about the carcinogenicity of agents. Some of the more common tests include mouse skin (Ingram and Grasso, 1991), transplacental and neonatal carcinogenesis (Ito, 1989), mammary gland tumor studies and preneoplastic lesions or altered cell foci (e.g., in liver, kidney, pancreas). Currently, increased research emphasis is being put on alternative approaches to the chronic rodent cancer bioassay. As an example, significant progress is being made using fish models (Bailey et al., 1984; Couch and Harshbarger, 1985).

2.6.4.4. Evaluation of Mechanistic Studies

The entire range of data about an agent's physical-chemical properties, structure-activity relationships to carcinogenic agents, and biological activity in vitro and in vivo is reviewed for mechanistic insights. The weight and significance of the observation of carcinogenic activity of the agent in vivo can be greatly influenced by the available data in several areas, all of which should be considered. Discussion should summarize available data on the agent's effects on DNA structure or expression and its effects on the cell cycle. Types of information to be considered include: whether the agent is a mutagenic or a non-mutagenic carcinogen, specific effects on proto-oncogenes or tumor suppressor genes and DNA transcription, and structural or functional analogies to agents with the above effects.

Information demonstrating effects on the cell cycle would include: mitogenesis, effects on differentiation, effects on cell death (apoptosis), tissue damage resulting in compensatory cell proliferation, receptor-mediated effects on growth-

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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signal transduction, and structural or functional analogies to agents with the above effects.

Information demonstrating effects on cell interaction might include: effects on contact inhibition of growth, intracellular communication, or immune reactions, and structural or functional analogies to agents with these effects.

These are not intended to be exclusive of other pertinent data not specifically listed. In addition, available data on the comparative pharmacokinetics and metabolism of the agent in animals and humans is assessed to consider whether similar mechanisms of action may be operating in humans and animals. (A similar summarization of evidence has been reported by IARC, 1991).

In evaluating carcinogenic potential and mechanism of action, analyses and conclusions based on short-term tests are accompanied by a discussion of the level of confidence that can be applied to all the data. The level of confidence is based on the following (not necessarily exclusive) factors: (a) the spectrum of endpoints relevant to carcinogenesis and the number of studies used for detecting each end point and consistency of the results obtained in different test systems and different species, (b) in vivo as well as in vitro observations, (c) the consistency and concordance of test results, (d) reproducibility of the results within a test system, (e) existence of a dose-response relationship, and (f) whether the tests are conducted in accordance with appropriate protocols agreed upon by experts in the field. For, example, a high level of confidence in describing the potential influence of an agent on carcinogenic events is based on results covering a number of events relevant to stages of carcinogenesis, a number of studies including in vivo tests showing consistent trends and good concordance. A low confidence data set is one that was sparse or has incongruous results and no clear data trends.

The strength of an hypothesis about mechanism of action generated by analysis of data in the above areas should be described by the following criteria:

a.

The operation of the mechanism in carcinogenesis must have been explained by a body of research data and have been generally accepted in the scientific community as a mechanism of carcinogenesis;

b.

There must be a body of experimental data that show how the agent in question participates in the mechanism of action. In the absence of data about the mechanism of action of an agent, decisions are made using default assumptions:

c.

That animal effects are relevant to human effects; and

e.

That the agent affects carcinogenesis with dose and response relating linearly at low exposure.

Both of these science policy assumptions are supported by current knowledge of carcinogenic processes, in the absence of better data. Each assumption must be examined in substance-specific risk assessments and replaced or joined by alternative analysis when adequate scientific data exist.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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2.7. Summary Of Experimental Evidence

{Criteria and examples for categorization of experimental evidence are major issues, particularly the weight of evidence contribution of research data of new kinds of genes and signal transduction pathways of growth control.}

A summary is made of all the experimental evidence that is relevant to human carcinogenic potential.

The confidence of an agent is potentially carcinogenic for humans increases as the number of animal species, strains, or number of experiments and doses showing a carcinogenic response increases. It also increases as the number of tissue sites affected by the agent increases and as the time to tumor occurrence or time to death with tumor decreases in dose-related fashion. Confidence also increases as the proportion of tumors that are malignant increases with dose and if the observed tumor types are historically rare in the species.

{The appropriate use of molecular biological data in the overall weight of evidence is a question. The strength of inferences to be drawn from data such as tumor susceptibility or gene effects is an unsettled issue.}

The weight of other experimental evidence increases or decreases the weight of findings relevant to human hazard in the following ways listed below. Findings in vivo add to the weight of evidence more rapidly than in vitro findings.

physical-chemical properties and structural or functional analogies can support inferences of potential carcinogenicity;

results in a number of short-term studies that are consistent can support inferences about potential human effects;

evidence of mutagenic effects on proto-oncogenes or tumor suppressor genes;

evidence of effects on cell growth signal transduction affecting cell division, differentiation; or cell death; and

induction of neoplastic behavioral characteristics in cells in culture or in vivo.

The summarization of experimental evidence refers only to the weight of evidence that an agent may or may not be carcinogenic in humans, not the dose-response relationship, which is the subject of a separate analysis.

The following four categories are used to summarize all of the experimental data relevant to inferences about human carcinogenic potential of an agent. Tumor responses that the Agency has found to be not relevant for inferring human hazard are not given weight. Other responses whose relevance is unresolved are noted in the categorization of evidence. Categorization is a matter of scientific

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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judgment, and the descriptions below are to be used as guidance in making that judgment, not as absolute criteria.

2.7.1. Category 1

The following examples illustrate persuasive evidence of carcinogenic potential. Other combinations of data also may be persuasive. In prospect, continued research on the role of agents in mutations of proto-oncogenes and tumor suppressor genes and related research on receptor-mediated effects on growth control genes also may provide persuasive data.

Examples:

1.

Long-term animal experiments showing increased malignant and benign tumors

 

a.

when the increased incidence of tumors is in more than one species or in more than one experiment (i.e., results are complicated with different routes of administration, or affect a range of dose levels)

   

-

at multiple sites, or

   

-

at a limited number of sites with a supporting weight of evidence from structure-activity analysis, or available short-term tests;

 

b.

when there is a response to an unusual degree in a single experiment with regard to high incidence of a low-incidence background tumor, unusual site or type of tumor, or early age at onset

   

-

with a dose-related increase in a highly malignant tumor or in early death with cancer, or

   

-

with a supporting weight of evidence from structure activity analysis or from available short-term studies; or

 

c.

in more than one experiment, at a single site

   

-

with a highly supportive weight of evidence from SAR analysis and numerous consistent findings of effects on carcinogenic processes in short-term studies, or

   

-

with a dose-related increase in tumor malignancy.

2.

Evidence that an agent is readily converted to a metabolite for which independent human or animal evidence is categorized as Group 1 and data are supportive of like pharmacokinetic disposition, or short-term studies of the agent are comparable in result with those of the metabolite.

3.

Short-term experiments that demonstrate an agent's influence on carcinogenic processes in vivo consistent with in vitro studies, SAR, and physical-chemical properties that are highly supportive of carcinogen activity. These are supported

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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by studies showing comparable metabolism and pharmacokinetics between study species and humans.

2.7.2. Category 2

Examples for this category include:

1.

A long-term animal experiment or experiments showing increased incidence of malignant tumors or combined malignant and benign tumors that falls short of the weight for categorization as Category 1.

2.

Evidence that an agent is readily converted to a metabolite for which independent human or animal evidence is Category 2 and data are supportive of like pharmacokinetic disposition, or short-term studies of the agent are comparable in result with those of the metabolite.

3.

Short-term studies and other evidence as described in 2.6.4.4. together with data supporting the likelihood of comparability in metabolism and pharmacokinetics between species.

2.7.3. Category 3

The experimental evidence does not support a conclusion either way about potential carcinogenicity because:

too few data are available;

evidence is limited to tumorigenicity and is found solely in studies in which the manner of administration (e.g., injection) or other aspects of study protocol present difficulties of interpretation; or

evidence of carcinogenicity is found at a single animal site in one species and sex in one or more experiments; the response is weak and without characteristics that give weight to a conclusion about potential human carcinogenicity.

For example, data are inconclusive if experimental data apart from the animal response do not support any positive inference about the agent's carcinogenic potential and if the animal response has a consistent pattern of most of the following characteristics:

At least two species have been tested, and the tumor response is seen only at the highest dose, in one sex, and one species.

The tumor incidence is predominantly benign and is seen only in one target organ.

The tumor is recognized as a common tumor type in that species, strain, and sex. In addition, the observed tumor rate, although statistically

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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significant in the experiment, is at or near the upper range of the historical control incidence.

The tumors do not cause death in the affected animals during the duration of the study and do not appear sooner in the treated animals than in the controls.

Such evidence may add some weight to results of the human studies.

2.7.4. Category 4

This summarization would apply when no increased incidence of neoplasms has been observed in at least two well-designed and well-conducted animal studies in different species including both sexes. The exposures are specified and the implication is that either the agent is not carcinogenic or the studies had insufficient power to detect an effect.

2.8. Human Hazard Characterization

Evidence from all of the elements of hazard assessment are drawn together for an overall characterization of potential human hazard as indicated in Figure 1.

2.8.1. Purpose and Content of Characterization

The major lines of observational human evidence and experimental evidence and reasoning are clearly described. Major judgments made in the face of conflicting data are particularly highlighted and explained, as are the assumptions or inferences made to address gaps in information. The strengths and weaknesses of the available data are described and related to resulting confidence in the characterization. The hazard characterization addresses not only the question of carcinogenic properties, but also, as data permit, the question of the conditions (dose, duration, route) under which these properties may be expressed.

To provide a basis for combining hazard and environmental exposure data in the final risk characterization, the hazard characterization points to differences expected according to route of exposure, if such differences can be determined. The assumption is made that the hazard is not route-specific, if this is reasonable and not contradicted by existing data. Information about the plausible mechanism or mechanisms of action is characterized and its implications for dose-response assessment are explained, including conditions of dose and duration.

2.8.2. Weight of Evidence for Human Carcinogenicity

{NOTE TO THE READER: The question as to whether to abandon our al-

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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phanumerical system entirely or merge it with a narrative statement has not been decided. We may retain labels of A, B, C, etc., labels for weight of evidence groups.}

A brief narrative statement is used to summarize the weight of evidence. It incorporates judgment about data from all elements of hazard assessment. A summary statement cannot resolve data interpretation issues; it can only focus judgments and help convey them. The purpose is to give the risk manager a sense of the evidence and of the risk assessor's confidence in the data and their interpretation for the assessment of human carcinogenicity potential and to allow comparison of weight of evidence judgments from case to case. A weight of evidence conclusion incorporates judgments both about overall confidence in a set of data as a basis for drawing conclusions and about the consistency and congruence of inferences supported by the set of data.

A weight of evidence conclusion is based both observational data from human studies and experimental data. All of the elements of analysis included in hazard assessment form the basis of judgment. The summarizations of experimental evidence and human evidence are ingredients for a weight of evidence statement. Note that animal tumor responses that the Agency considers not relevant for inferring human hazard are not weighed. However, unresolved questions about relevance are all noted and considered in the statement.

As the first step, a decision is made on whether the evidence is adequate or not adequate for characterization. ''Not adequate" means that the existing data are inadequate overall to support a conclusion because either there are too few data or the data are flawed due to experimental design or conduct, or because findings are not substantial enough to support inferences either way about potential human carcinogenicity. Typically, human or experimental data that are in Category 3 would be considered as not adequate for characterization.

If the evidence is adequate for a weight-of-evidence determination, it is described within a narrative statement. The narrative statement explains the weight of evidence by summarizing the content and contribution of individual lines of evidence and explaining how they combine to form the overall weight of evidence. The statement highlights the quality and extent of data and the congruence, or lack of congruence, of inferences they support. The statement also highlights default assumptions used to address gaps in knowledge.

The statement gives the weight of evidence by route of exposure, pointing out the basis of anticipated differences and whether the default assumption supporting extrapolation of hazard potential between routes has been used and is appropriate. Anticipated potency differences by route are pointed out, based on comparatively poor to ready absorption by different routes (see § 2.6.3. Metabolism and Pharmacokinetics).

The statement discusses the data implications for mechanism of action. It recommends a general approach or approaches for dose-response assessment in

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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image

FIGURE 1

accordance with what the hazard data imply about the nature of dose-response below the range of observation of available studies. A weight of evidence for hazard by any mechanism is characterized. Thus, for example, an agent that is estrogenic and not likely to cause permanent genetic changes is characterized as a carcinogenic hazard, with any limitations of dose being explained in the narrative statement. The quantitative dose-response estimation or shape of the dose-response curve does not affect the weight of evidence for hazard.

The statement notes whether its source is an individual EPA office or an EPA consensus. The overall conclusion is noted by use of one of the following descriptors: "known," highly likely," or "likely" to be a human carcinogen; "some evidence'' or "not likely to be a human carcinogen at exposure levels studied or alternately under conditions of environmental exposure." These descriptors fall along a continuum of likelihood that an agent has human carcinogenic potential. More than one descriptor may apply to a single agent if the weight of evidence differs by route of administration. Also, two descriptors may

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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be applied if the evidence for a route is judged to fall between two descriptors. These standard descriptors are provided for the purpose of maintaining consistency of expression of conclusions from case to case. The text of the narrative statement as a whole is the primary means of conveying information on the weight of evidence.

2.8.2.1. Descriptors

{The number of descriptor categories for total weight of evidence is a continuing issue. The evidence is along a continuum. How many descriptors are needed to represent the continuum? What are the criteria for establishing them?}

Explanations of the general levels of evidence associated with descriptors in terms of the summarizations of evidence made in the course of a hazard assessment are as follows:

"Known" to be carcinogenic in humans is a statement that evidence is convincing (Category 1) that the agent has observed carcinogenic effects in humans by a specified route or routes of exposure.

"Highly likely" is a statement that:

1.

there is persuasive experimental evidence of carcinogenicity (Category 1) and suggestive human evidence (Category 2), or

2.

there is persuasive experimental evidence (Category 1) showing a very strong animal response (multiple tumor sites in more than one species), or

3.

an agent is known to be a carcinogen in humans by one route of exposure (known) is also absorbed by another route, making carcinogenic effects "highly likely" by the second route.

"Likely" is a statement that:

1.

there is persuasive experimental evidence (Category 1), or

2.

there is suggestive evidence from human data (Category 2) with experimental evidence (Category 2) that supports the likelihood that the human effects seen were due to the agent in question.

"Some evidence" is a statement that:

1.

there is experimental evidence (Category 2), or

2.

suggestive human evidence (Category 2).

However, the totality of the evidence is weak because findings are inconsistent, or there are many gaps in the data.

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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"Not likely to be a human carcinogenic at exposure levels studied or alternately, under conditions of environmental exposure" is a statement that:

1.

human evidence has been summarized as no evidence at exposure levels studied (Category 4), and there are no positive animal findings, or

2.

experimental evidence has been summarized as no evidence at exposure levels studied (Category 4), and there are no positive human findings, or

3.

the occurrence of carcinogenic effects is not expected for a particular route of human environmental exposure (oral, dermal, inhalation) because the agent is not absorbed by that route, or

4.

the mechanism of carcinogenicity of an agent operates only at doses above the range of plausible environmental exposure, e.g., carcinogenesis as a secondary effect of another effect that occurs only at high doses, or

5.

the occurrence of carcinogenic effects depends on administration of the agent in a manner that has no parallel with plausible environmental exposure, e.g., injection of polymers.

This descriptor is explained in the narrative statement as being applicable only to the specific exposure levels studied or environmental exposure conditions which are given in the statement.

2.8.2.2. Examples of Narrative Statements
Compound X

Following review of all available data relevant to the potential human carcinogenic hazard of X (CAS # 000001), the … Office of EPA concludes that X is not likely to be carcinogenic to humans by any route of exposure at environmental levels. This determination is based on experimental evidence. No human studies on X are available for evaluation. The evidence supporting this finding is the animal response.

With dietary administration, X caused a statistically significant increase in the incidence of urinary bladder hyperplasia and tumors (urinary bladder transitional cell papillomas and carcinomas) in male but not in female Charles River CD rats at high dose levels (›30,000 ppm). The tumors were seen only at dose levels producing calculi in the kidneys, ureters and the urinary bladder. The presence of the urinary bladder calculi was associated with a decrease in the urinary pH. The urinary bladder calculi were almost always associated with urinary bladder hyperplasia (›90%). A major metabolite of X did not cause any increase

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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in tumor incidence in another bioassay in rats. X was not carcinogenic in mice in well-conducted experiments.

The in vivo (mouse micronucleus test) and in vitro (in bacteria and yeast) short term- studies on X indicate with medium confidence that X is not genotoxic. Structure-activity-relationship analysis reveals no chemicals which are related to X and also induce tumors. It is concluded that the tumor response in male rats was secondary to stone formation at high doses, and may be a phenomenon unique to the male rats. No dose-response analysis is recommended unless a high-dose environmental exposure to humans is discovered.

Compound Y

Following review of all available data relevant to the potential human carcinogenic hazard of Y (CAS # 000002), EPA concludes that Y is likely to be carcinogenic to humans by all routes of exposure. This determination is based on experimental evidence. No human studies are available for evaluation. The strongest lines of evidence supporting findings on Y are animal experiments and structure-activity relationships.

Rodent studies showed statistically significant increases in the incidence of liver tumors (hepatocellular adenomas and carcinomas combined) in two strains of mice, in two independent and adequately conducted studies. The increases of liver tumors occurred at high and low doses. Y also produced a statistically significant increase in stomach tumors (papillomas) in both male and female mice at a dose also producing significant mortality and reduced body weight (-18% to -23% throughout the study) and the presence of white foci and ulcers in the stomach of occasional animals.

Y, administered orally, did not induce tumors in F344 rats in an adequately conducted study. Data from acute inhalation toxicity and dermal absorption studies show that Y is absorbed by both dermal and inhalation exposure.

Y caused gene mutations and chromosome aberrations in D. melanogaster and DNA damage in yeast, but it did not induce mutagenic effects in either in vitro or in vivo mammalian systems. The mutagenicity data set is of low confidence, and it neither supports nor contradicts inferences about carcinogenicity. In addition, it does not suggest a mechanism of action.

Structure-activity relationship analysis shows that Y is very closely re-

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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lated in structure to eight other chemicals, all of which produce liver tumors in mice, rats, or both.

Based upon the above analysis, it is suggested that the dose-response analysis employ a default assumption of linearity at low dose and consider the liver tumor in mice as an appropriate endpoint.

3. Dose-Response Assessment

3.1. Purpose And Scope Of Dose-Response Assessment

Dose-response assessment tests the hypothesis that an agent has produced an effect and portrays the relationship between the agent and the response elicited. In risk assessments, dose and response observations from experimental or epidemiological studies are often projected to much lower exposure levels encountered in the environment.4 In addition, the mathematical models used for extrapolation are based on general assumptions about the nature of the carcinogenic process. These assumptions may be untested for the particular agent being evaluated (Kodell, in press). If the dose-response relationship is developed from an experimental animal study, it also must be extrapolated from animals to humans. Because of these inherent uncertainties, projections well outside the range of the observed data are treated as bounding estimates, not as true values. Information that shows a comparable pharmacokinetic and metabolic response to an agent in humans and animals greatly increases confidence in the dose-response analysis. Data suggesting that an agent works through a common mechanism of action in humans and animals also greatly increases confidence in the low dose extrapolation. In the absence of such data, default approaches provide upper-bound estimates of response at low doses, with a lower limit as small as zero at very low doses.

In the absence of dose-response data on members of a class of agents, it may be possible to construct a set of toxicity equivalence factors (TEF) to be used to

4For this discussion, "exposure" means contact of an agent with the outer boundary of an organism. "Applied dose" means the amount of an agent presented to an absorption barrier and available for absorption; "internal dose" means the amount crossing an absorption barrier (e.g., the exchange boundaries of skin, lung, and digestive tract) through uptake processes; and the amount available for interaction with an organ or cell is the "delivered dose'' for that organ or cell. For more detailed discussion see Exposure Assessment Guidelines __ FR ___ (1992).

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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quantify dose-response by reference to an already-characterized member of the class.

3.2. Elements of Dose-Response Assessment

The elements of dose response analysis include selection of response data and dose data, followed by a stepwise dose-response analysis. The first step in the dose-response analysis is fitting of the data in the range of study observation; the second step, if needed, is extrapolation of the dose-response relationship to the range of the human exposure of interest.

A dose-response assessment should take advantage of available data to support a more confident analysis. When data gaps exist, assumptions based on current knowledge about the biological events in carcinogenesis and pharmacokinetic processes are used.

3.2.1. Response Data

Appropriate response data, as well as mechanistic information from the hazard characterization, are applied in the dose-response assessment. The quality of the data and their relevance to human exposure are important selection considerations.

If adequate positive human epidemiologic data are available, they are usually the preferred basis for analysis. Positive data are analyzed to estimate response to environmental exposure in the observed range. (USEPA, 1992a). Extrapolation to lower environmental exposure ranges is carried out, as needed. If adequate exposure data exist in a well-designed and well-conducted epidemiologic study that detects no effects, it may be possible to obtain an upper-bound estimate of the potential risk. Animal-based estimates, if available, are also presented, and the animal results are compared with the upper-bound estimate from human data for consistency.

When animal studies are used, response data from a species that responds most like humans should be used, if information to this effect exists. When an agent was tested in several experiments involving different animal species, strains, and sexes at several doses and different routes of exposure, the following approach to selecting the data sets is generally used:

a.

The tumor incidence data are separated into data sets according to organ site and tumor type.

b.

All biologically and statistically acceptable data sets are examined.

c.

Data sets are analyzed with regard to route of exposure.

d.

A judgment is reached based on biological criteria as to which set or sets best represents the body of data for the purpose of estimating human response. This judgment is augmented with judgment as to the statistical suitability of the data for modeling in the experimental data

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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range. The hazard characterization is the point of reference for the initial judgment. The following characteristics of a data set favor its selection.

 

high quality of study protocol and execution;

 

malignant neoplasms;

 

earlier onset of neoplasm;

 

greater number of data points to define the relationship of dose and response;

 

background incidence in test animal is not unusually high;

 

most sensitive-responding species are used; or

 

data on a related effect (e.g., DNA adduct formation) or mechanistic data to augment the tumor.

Appropriate options for presenting results include use of a single data set, combining data from different experiments (Stiltler et al., 1992), showing a range of results from more than one data set, representing total response in a single experiment by combining animals with tumors or a combination of these options. The rationale for selecting an approach is presented, including the biological and statistical considerations involved. The objective is to provide a best judgment of how to represent the observed data.

Benign tumors are usually combined with malignant tumors for risk estimation if the benign tumors are considered to have the potential to progress to associated malignancies of the same histogenic origin. (McConnell, 1986). When tumors are thus combined, the contribution to the total risk of benign tumors is indicated. The issue of how to consider the contribution of the benign tumors should be discussed in the dose-response characterization and risk characterization.

Data on certain endpoints related to tumor induction may be used to extend dose-response analysis below the relatively high dose range in which tumors are observable. These data permit extension of the curve-fitting analysis (Swenberg et al., 1987) and may provide parameters for applying a mechanism-based model (US EPA Dioxin Assessment, 1992c). Data might include information on receptor binding, DNA adduct formation, physiological effects such as disruption of hormone activity, or agent-specific alterations in cell division rates. In considering whether such endpoints can be applied, key issues are confidence that the data reflect carcinogenic effects of the agent and that these have been well measured with a dose-effect trend.

3.2.2. Dose Data

Regardless of the source, animal experiments or epidemiologic studies, several questions need to be addressed in arriving at an appropriate measure of dose. One question is whether data are sufficient to estimate internal dose or delivered

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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dose. Part of this question is whether the parent compound, a metabolite, or both agents are closer in a metabolic pathway to a carcinogenic form.

The delivered dose to target is the preferred measure of dose. In practice, there may be little or no information on the concentration or identity of the active agent at a site of action; thus, being able to compare the applied and delivered doses between routes and species is an ideal that is rarely attained. Even so, incorporating data to the extent possible is desirable.

Even if pharmacokinetic and metabolic data are sufficient to derive a measure of delivered dose to the target, the dose-response relationship is also affected by kinetics of reactions at the target (pharmacodynamics) and by other steps in the development of neoplasia. With few exceptions, these processes are currently undefined.

The following discussion assumes that the analyst will have data of varying detail in different cases about pharmacokinetics and metabolism. Approaches to limited data are outlined as well as approaches and judgments for more sophisticated analysis based on additional data.

3.2.2.1. Base Case — Few Data

Where there are insufficient data available to define the equivalent delivered dose between species, it is assumed that delivered doses at target tissues are directly proportional to applied doses. This assumption rests on the similarities of mammalian anatomy, physiology, and biochemistry generally observed across species. This assumption is more appropriate at low applied dose concentrations where sources of nonlinearity, such as saturation or induction of enzyme activity, are less likely to occur.

The default procedure is to scale daily applied doses experienced for a lifetime in proportion to body weight raised to the 3/4 power (W3/4). Equating exposure concentrations in parts per million units for air, food, or water is an alternative version of the same default procedure because daily intakes of these are in proportion to W3/4. The rationale for this factor rests on the empirical observation that rates of physiological processes consistently tend to maintain proportionality with W3/4. A more extensive discussion of the rationale and data supporting the Agency's adoption of this scaling factor can be found in (USEPA, 1992b).

The differences in biological processes among routes of exposure (oral, inhalation, dermal) can be great, due to, for example, first pass effects and differing results from different exposure patterns. There is no generally applicable method for accounting for these differences in uptake processes in quantitative route-to-route extrapolation of dose-response data in the absence of good data on the agent of interest. Therefore, route-to-route extrapolation of dose data will be based on a case-by-case analysis of available data. When good data on the agent itself are limited, an extrapolation analysis can be based on expectations from

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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physical chemical properties of the agent, properties and route-specific data on structurally analogous compounds, or in vitro or in vivo uptake data on the agent. Route-to-route uptake models may be applied if model parameters are suitable for the compound of interest. Such models are currently considered interim methods; further model development and validation is awaiting the development of more extensive data (see generally, Gerrity and Henny, 1990).

3.2.2.2. Pharmacokinetic Analyses

Physiologically based mathematical models are potentially the most comprehensive way to account for pharmacokinetic processes affecting dose. Models build on physiological compartmental modeling and attempt to incorporate the dynamics of tissue perfusion and the kinetics of enzymes involved in metabolism of an administered compound.

A comprehensive model requires the availability of empirical data on the carcinogenic activity contributed by parent compound and metabolite or metabolites and data by which to compare kinetics of metabolism and elimination between species. A discussion of issues of confidence accompanies presentation of model results (Monro, 1991). this includes considerations of model validation and sensitivity analysis that stress the predictive performance of the model. Another assumption made when a delivered dose measure is used in animal-to-human extrapolation of dose-response data is that the pharmacodynamics of the target tissue(s) will be the same in both species. This assumption should be discussed, and confidence in accepting it should be considered in presenting results.

Pharmacokinetic data can improve dose-response assessment by accounting for sources of change in proportionality of applied-to- internal dose or to delivered dose at various levels of applied dose. Many of the sources of potential nonlinearity involve saturation or induction of enzymatic processes at high doses. An analysis that accounts for nonlinearity (for instance, due to enzyme saturation kinetics) can assist in avoiding over estimation or under estimation of low dose if extrapolation is from a sublinear or supralinear part of the experimental dose-response curve. (Gillette, 1983). Pharmacokinetic processes tend to become linear at low doses, an expectation that is more robust than low-dose linearity of response (Hattis, 1990). Thus, accounting for nonlinearities allows better description of the shape of the curve at higher levels of dose, but cannot determine linearity or nonlinearity of response at low dose levels (Lutz, 1990; Swenberg et al., 1987).

3.2.2.3 Additional Considerations for Dose in Human Studies

The applied dose in a human study has uncertainties because of the exposure fluctuations that humans experience compared with the controlled exposures

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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received by animals on test. In a prospective cohort study, there is opportunity to monitor exposure and human activity patterns for a period of time that supports estimation of applied dose (USEPA, 1992a). In a retrospective cohort study, exposure is based on human activity patterns and levels reconstructed from historical data, contemporary data, or a combination of the two. Such reconstruction is accompanied by analysis of uncertainties considered with sensitivity analysis in the estimation of dose (Wyzga, 1988; USEPA, 1986). These uncertainties can also be assessed for any confounding factor, for which a quantitative adjustment of dose-response data is made (USEPA, 1984).

Exposure levels of groups of people in the study population often are represented by an average when they are actually in a range. The full range of data are analyzed and portrayed in the dose-response analysis when possible (USEPA, 1986).

The cumulative dose of an agent is commonly used when modeling human data. This can be done, as in animal studies, with a default assumption in the absence of data that support a different dose surrogate. Given data of sufficient quality, dose rate or peak exposure can be used as an alternative surrogate to cumulative dose.

3.3 Selection Of Quantitative Approach

Because risks at relatively low exposure levels generally cannot be measured directly either by animal experiments or by epidemiologic studies of reasonable sample size, a number of mathematical models have been developed to extrapolate from high to low dose. Different extrapolation models may fit the observed data reasonably well but may lead to large differences in the projected risk at lower doses. As was pointed out by OSTP (1985 see Principle 26), no single mathematical procedure is recognized as the most appropriate for low-dose extrapolation in carcinogenesis. Low-dose extrapolation procedures use either mechanistic or empirical models. When sufficient biological information exists to identify and describe a mechanism of action, low-dose extrapolation may be based on a mathematical representation of the mechanism. When the mechanism is unknown or information is limited, low-dose is derived from an empirical fit of a curve compatible with the available information.

If a carcinogenic agent acts by accelerating the same carcinogenic process that leads to the background occurrence of cancer, the added effect on the population at low doses marginally above background level is expected to be linear. Above background level, the population response may continue to be linear in the case of an agent acting directly on DNA, or the population response may be influenced by individual variability in sensitivity to phenomena such as disruption of hormone homeostasis or receptor-mediated activity. If the agent acts by a mechanism with no endogenous counterpart, a population response threshold may exist (Crump et al., 1976; Peto, 1978; Hoel, 1980; Lutz, 1990). The

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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Agency reviews each assessment as to the evidence on carcinogenesis mechanisms and other biological or statistical evidence that indicates the suitability of a particular extrapolation model. When longitudinal data on tumor development are available, time-to-tumor or survival models may be used and are preferred. In all cases, a rationale is included to justify the use of the chosen model.

The goal in choosing an approach is to achieve the closest possible correspondence between the approach and the view of the agent's mechanism of action developed in the hazard assessment. If the hazard assessment describes more than one mechanism as plausible and persuasive given the data available, corresponding alternative approaches for dose-response analysis are considered.

3.3.1. Analysis in the Range of Observation

In portraying dose response in the range of observed data, analyses incorporate as much reliable information as possible. Pharmacokinetic data or interspecies scaling is used to derive human-equivalent measures of the animal-administered dose. The empirical response data analyzed include tumor incidence data augmented, if possible, by incidence data on effects leading to the tumor response, e.g., DNA adduct or other effect-marker data (Swenberg, 1987).

Dose-response models span a hierarchy that reflects an ability to incorporate different kinds of information. If data to support it are available, a mechanism-based procedure is the preferred approach for modeling. A mechanism-based procedure is explicitly devised to reflect biological processes. Theoretical values for parameters, e.g., theoretical cell proliferation rates, are not used to enable application of a mechanism-based model (Portier, 1987). If such data are absent, a mechanism-based model is not used. An example of a mechanism-based model is the receptor mediated toxicity model for dioxin, under development at EPA (U.S. EPA, 1992c).

Dose-response models based on general concepts of a mechanism of action are next in amount of information required. For a specific agent, model parameters are obtained from laboratory studies. Examples are the two-stage models of initiation, clonal expansion, and progression developed by Moolgavkar et al. (1981) and Chen et al. (1991). Such models require extensive data to build the form of the model as well as to estimate how well it conforms with the observed carcinogenicity data.

Empirical models, which do not incorporate information about mechanism of action, form the rest of the hierarchy. Among these, time-to-tumor models incorporate longitudinal information on tumor development. Simple quantal models use only the final incidence at each dose level. The linearized multistage procedure is an example of an empirical model.

If a mechanism-based model is judged to be not suitable, the analysis uses an empirical model whose underlying parameters correspond to the putative mechanism of action identified in the hazard characterization. A multistage

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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model (Zeise et al., 1987) structured with time to response as the random variable is appropriate when time is the dominant factor for probability of response. This is the approach when available information described in the hazard characterization is consistent with an assumption that there is no threshold of response for individuals. When the probability of effect is due to the distribution of thresholds for individuals in the population, a model considering dose as the random variable may be used. This may be considered an appropriate approach when the mechanism has been identified as one such as disruption of hormone homeostasis.

{The issue of appropriate dose-response models is still under discussion at EPA.}

Ordinarily, models are expected to provide an adequate fit to the observed dose-response information. The outcome of most tests of goodness of fit to the observations is not an effective means of discriminating among models that all provide an adequate fit. Although a model may adequately fit the observed dose-response information, all models have limitations in their ability to describe the underlying processes and make projections outside the observed information. A prime consideration is the potential for model error, that is the possibility that a model might appear to fit the observed data but be based on an inadequate mathematical description of the true underlying mechanism. This is especially crucial when making inferences outside the range of observation, as alternative models may provide an adequate fit to the observed information but have substantially different implications outside the range of observation.

Sometimes an inadequate fit might be improved by incorporating more information. For example, data in which there is high mortality may be poorly fit unless competing risks of death by toxicity are taken into consideration with time-to-tumor information and survival adjustments. If an adequate fit cannot be obtained, it may be necessary to give less weight to the observations most removed from low-dose risk., e.g., from the highest dose level in a study with several dose levels.

Statistical considerations can affect the precision of model estimates. These include the number and spacing of dose levels, sample sizes, and the precision and accuracy of dose measurements. Sensitivity analysis can be performed to describe the sensitivity of the model to slight variations in the observed data. A large divergence between upper and lower confidence bounds indicates that the model cannot make precise projections in that range. All of these considerations are important in determining the range in which a model is supported by data.

With the recent expansion of readily available computing capacity, computer-intensive methods are being adapted to create simulated biological data that are comparable with the observed information. These simulations can be used for sensitivity analysis, for example, to analyze how small, plausible variations

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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in the observed data could affect the risk estimates. These simulations can also provide information about experimental uncertainty in risk estimates, including a distribution of risk estimates that are compatible with the observed data. Because these simulations are based on the observed data, they cannot, however, assist in evaluating the extent to which the observed data as a whole are idiosyncratic rather than typical of the true state of risks.

The lowest reliable area of a curve is identified as a result of the data modeling. This point is generally at the level of not less than a 1.0 percent response if only animal tumor response data are available. (This 1.0 percent response level is about an order of magnitude below the potential power of a standard rodent study to detect effects.) The lowest reliable area may be extended below a 1.0 percent response if based on a more powerful study, on combined studies, or on joining the analysis of tumor response data with data on other markers of effect. This lowest reliable area provides an estimate that can be used for comparision with similar analyses of the observed range of noncancer effects of an agent (USEPA, 1991f).

3.3.2 Extrapolation

Using the lowest reliable point from the first step of analysis as a point of departure, the preferred approach for this second step of analysis still is a mechanism-based model, if data support it. If a mechanism-based model has been used to portray the observed data, the question in this step is whether confidence in the model extends to using it for extrapolation. If data are insufficient to support a mechanism-based model, extrapolation is done by a default procedure whose parameters reflect the general mechanism or mechanisms of action considered to be supported by the available biological information.

If the mechanism of action being considered leads to an expected linear dose-response relationship, the linearized multistage model or a model-free approach may be appropriate (Gaylor and Kodell, 1980; Krewski, 1984; Flamm and Winbush, 1984).

The mechanism of action being considered may project that the dose-response relationship in the population is most influenced by the differences in sensitivities. In this case, a model including tolerance distribution parameters may be used to provide estimates of the proportion of the population at risk for specific doses of interest, e.g., 1/1000, 1/10000 lifetime risk levels. This approach requires data for a mathematical portrayal of the distribution.

{NOTE: The appropriate empirical modeling approaches for extrapolation are an undecided issue when a putative mechanism of action has been recognized but data are not supportive of a mechanism-based model. Further technical analysis and discussion are necessary before this section can be completed.}

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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Alternatively, the mechanism may be one that involves a population threshold. In these cases, extrapolation is not made. Instead, a "margin of exposure" presentation is made in the risk characterization. The margin of exposure in this context is the lowest reliable dose-response area from observed data divided by the environmental dose level of interest.

3.3.3 Issues for Analysis of Human Studies

Issues and uncertainties arising in dose-response assessment based on epidemiological studies are analyzed in each case. Several sources of uncertainty need to be addressed in the dose-response analysis. Consideration needs to be given to the data on the exposure and mortality experience of the study population and of the population that will represent the background incidence of the neoplasm(s) involved. In this area, there are potentials for mistakes or uncertainty in the data or adjustments to the data concerning the occurrence or level of exposure of the population members, mortality experience of a population, incomplete follow-up of individuals, exposure (or not) of individuals to confounding causes, or consideration of latency of response. These are assessed by analyzing the sensitivity of dose-response study results to errors where data permit. Other kinds of uncertainty can occur because of small sample size which can magnify the effects of misclassification or change assumptions about statistical distribution that underlie tests of statistical significance (Wyzga, 1988). These uncertainties are discussed. Where possible, analyses of the sensitivity of results to the potential variability in the data in these areas are performed.

The suitability of various available mathematical procedures for quantifying risk attributed to exposure to the study agent is discussed. These methods (e.g., absolute risk, relative risk, excess additive risk) account differently for duration of exposure and background risk, and one or more can be used in the analysis as data permit. The use of several of these methods is encouraged when they can be used appropriately in order to gain perspectives on study results.

3.3.4. Use of Toxicity Equivalence Factors

A toxicity equivalence factor (TEF) procedure is one used to derive quantitative dose-response estimates for agents that are members of a category or class of agents. TEFs are based on shared characteristics that can be used to order the class members by carcinogenic potency when cancer bioassay data are inadequate for this purpose (USEPA, 1991c). The ordering is by reference to the characteristics and potency of a well-studied member or members of the class. Other class members are indexed to the reference agent(s) by one or more shared characteristic to generate their TEFs. The TEFs are usually indexed at increments of a factor of 10. Very good data may permit a smaller increment to be used. Shared characteristics that may be used are, for example, receptor-binding

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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characteristics, results of assays of biological activity related to carcinogenicity, or structure-activity relationships.

TEFs are generated and used for the limited purpose of assessment of agents or mixtures of agents in environmental media when better data are not available. When better data become available for an agent, its TEF should be replaced or revised.

Guiding criteria for the successful application of TEFs are (USEPA, 1991c):

1.

A demonstrated need. A TEF procedure should not be used unless there is a clear need to do so.

2.

A well-defined group of chemicals.

3.

A broad base of toxicological data.

4.

Consistency in relative toxicity across toxicological endpoints.

5.

Demonstrated additivity between toxicities of group members for assessment of mixtures.

6.

A mechanistic rationale.

7.

Consensus among scientists.

3.4. Dose-Response Characterization

The conclusions of dose-response analysis are presented in a characterization section. Because alternative approaches may be plausible and persuasive in selecting dose data, response data, or extrapolation procedures, the characterization presents the judgments made in such selections. The results for the approach or approaches chosen are presented with a rationale for the one(s) that is considered to best represent the available data and best correspond to the view of the mechanism of action developed in the hazard assessment.

The exploration of significant uncertainties in data for dose and response and in extrapolation procedures is part of the characterization. They are described quantitatively if possible through sensitivity analysis and statistical uncertainty analysis. If quantitative analysis is not possible, significant uncertainties are described qualitatively. Dose-response estimates are appropriately presented in ranges or as alternatives when equally persuasive approaches have been found.

Numerical dose-response estimates are presented to one significant figure and qualified as to whether they represent central tendency or plausible upper-bounds on risk or, in general, as to whether the direction of error is to overestimate or under estimate risk. For example, the straight line extrapolation used as a default is typically considered to place a plausible upper- bound on risk at low doses. On the other hand, a tolerance distribution model used as a default to portray risk-specific response distribution of the population may greatly underestimate risks if the mechanism is in fact a linear, nonthreshold one. (Krewski, 1984).

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In cases, where a mechanism has been identified that has special implications for early-life exposure, differential effects by sex, or other concerns for sensitive subpopulations, these are explained. Similarly, any expectations that high dose-rate exposures may alter the risk picture for some portion of the population are described. These and other perspectives are recorded to guide exposure assessment and risk characterization.

4. Exposure Assessment

Guidelines for exposure assessment of carcinogenic and other agents are published in USEPA, 1992a. The exposure characterization is a key part of the exposure assessment; it is the summary explanation of the exposure assessment. The exposure characterization

a.

provides a statement of purpose, scope, level of detail, and approach used in the assessment;

b.

presents the estimates of exposure and dose by pathway and route for individuals, population segments, and populations in a manner appropriate for the intended risk characterization;

c.

provides an evaluation of the overall quality of the assessment and the degree of confidence the authors have in the estimates of exposure and dose and the conclusions drawn; and

d.

communicates the results of exposure assessment to the risk assessor, who can then use the exposure characterization, along with the characterization of the other risk assessment elements, to develop a risk characterization.

In general, the magnitude, duration, and frequency of exposure provide fundamental information for estimating the concentration of the carcinogen to which the organism is exposed. These data are generated from monitoring information, modeling results, and or reasoned estimates. An appropriate treatment of exposure should consider the potential for exposure via ingestion, inhalation, and dermal penetration from relevant sources of exposures, including multiple avenues of intake from the same source.

Special problems arise when the human exposure situation of concern suggests exposure regimens, e.g., route and dosing schedule that are substantially different from those used in the relevant animal studies. The cumulative dose received over a lifetime, expressed as average daily exposure prorated over a lifetime, is an appropriate measure of exposure to a carcinogen particularly for an agent that acts by damaging DNA. The assumption is made that a high dose of a carcinogen received over a short period of time is equivalent to a corresponding low dose spread over a lifetime. This approach becomes more prob-

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lematic as the exposures in question become more intense but less frequent, especially when there is evidence that the agent acts by a mechanism involving dose-rate effects.

5. Characterization Of Human Risk

5.1. Purpose

The risk characterization is prepared for the purpose of communicating results of the risk assessment to the risk manager. Its objective is to be an appraisal of the science that the risk manager can use, along with other decisionmaking resources, to make public health decisions. A complete characterization presents the risk assessment as an integrated picture of the analysis of the hazard, dose response, and exposure. It is the risk analyst's obligation to communicate not only summaries of the evidence and results, but also perspectives on the quality of available data and the degree of confidence to be placed in the risk estimates. These perspectives include explaining the constraints of available data and the state of knowledge about the phenomena studied.

5.2. Application

A risk characterization is a necessary part of any Agency report on risk, whether the report is a preliminary one prepared to support allocation of resources toward further study or a comprehensive one prepared to support regulatory decisions. Even if only parts of a risk assessment (hazard and dose-response analyses for instance) are covered in a document, the risk characterization will carry the characterization to the limits of the document's coverage.

5.3. Content

Each of the following subjects should be covered in the risk characterization.

5.3.1. Presentation and Descriptors

The presentation of the results of the assessment should fulfill the aims as outlined in the purpose section above. The summary draws from the key points of the individual characterizations of hazard, dose response, and exposure analysis performed separately under these guidelines. The summary integrates these characterizations into an overall risk characterization (AIHC, 1989).

The presentation of results clearly explains the descriptors of risk selected to

Suggested Citation:"Appendix D: Working Paper for Considering Draft Revisions to the U.S. EPA Guidelines for Cancer Risk Assessment." National Research Council. 1994. Science and Judgment in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2125.
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portray the numerical estimates. For example, when estimates of individual risk are used or population risk (incidence) is estimated, there are several features of such estimates that risk managers need to understand. They include, for instance, whether the numbers represent average exposure circumstances or maximum potential exposure. The size of the population considered to be at risk and the distribution of individuals' risks within the population should be given. When risks to a sensitive subpopulation have been identified and characterized, the explanation covers the special characterization of this population.

5.3.2. Strengths and Weaknesses

The risk characterization summarizes the kinds of data brought together in the analysis and the reasoning upon which the assessment rests. The description conveys the major strengths and weaknesses of the assessment that arise from availability of data and the current limits of understanding of the process of cancer causation. Health risk is a function of the three elements of hazard, dose response, and exposure. Confidence in the results of a risk assessment is, thus, a function of confidence in the results of the analyses of each element. The important issues and interpretations of data are explained, and the risk manager is given a clear picture of consensus or lack of consensus that exists about significant aspects of the assessment. Whenever more than one view of the weight of evidence or dose-response characterization is supported by the data and the policies of these guidelines, and when choosing between them is difficult, the views are presented together. If one has been selected over another, the rationale is given; if not, both are presented as plausible alternative results. If a quantitative uncertainty analysis of data is appropriate, it is presented in the risk characterization; in any case, qualitative discussion of important uncertainties is appropriate.

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The public depends on competent risk assessment from the federal government and the scientific community to grapple with the threat of pollution. When risk reports turn out to be overblown--or when risks are overlooked--public skepticism abounds.

This comprehensive and readable book explores how the U.S. Environmental Protection Agency (EPA) can improve its risk assessment practices, with a focus on implementation of the 1990 Clean Air Act Amendments.

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This comprehensive volume will be important to the EPA and other agencies, risk managers, environmental advocates, scientists, faculty, students, and concerned individuals.

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