Drinking Water and Health, Volume 6 (1986) / Chapter Skim
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8. Risk Assessment
8. Risk Assessment
Pages 250-293
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From page 250... ...
In this chapter, the committee first reviews the discussions of risk assessment set forth by previous Safe ~ng Water Committees. It then examines three topics common to all risk assessment: estimation of exposure from various sources and by different routes, pharmacokinetics, and interspecies extrapolation.
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From page 251... ...
. Problems that lie at the interface of science and policy include selection of test method, selection of animal data and bioassay results for use as the basis for extrapolation to humans, determination of how one should use data on so-called benign as well as malignant tumors, selection of appropriate safety factors for developing standards, and selection of the mathematical model to be used for extrapolation.
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From page 252... ...
Since 1977, when the first Safe Drinking Water Committee conducted QRAs on waterborne carcinogens, National Research Council committees have consistently highlighted limitations of the methodology (NRC, 1977, 1980, 1983~. This committee endorses attempts to develop, validate, and apply QRA techniques to the evaluation of potential noncancer toxic responses, such as neurotoxicity, reproductive toxicity, and developmental toxicity, as well as liver damage, kidney damage, and respiratory responses other than lung cancer.
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From page 253... ...
If a threshold cannot be shown, the acceptable dose must be related to the data from animal experimentation and consideration of the seriousness of the toxic effects, as well as the likelihood and ease of reversibility, the variability of the sensitivity of the exposed population, and the economic and health-related importance of the material" (NRC, 1977, pp.
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From page 254... ...
Moreover, it tends to be conservative in that at low doses it will give higher estimates of the unknown risk than will many others. More confidence would be placed in mathematical models for extrapolation if they incorporated biological characteristics such as pharmacokinetic data and timeto-occurrence of tumors.
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From page 255... ...
, the computations presented in the present volume are based on the generalized form of the model. In considering the appropriate scaling for extrapolating data from the laboratory to humans, the 1980 committee remarked: The practice among cancer chemotherapists of basing dose on body surface area is useful, particularly for extrapolation from small animals to humans, and is supported by a sizeable body of experimental evidence.
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From page 256... ...
. and it appears sensible to assume this until proved otherwise." Berenbaum also noted that the "effect of a marked antagonism is to produce a threshold in the curve." Reliability of Risk Estimation Considering all the variables encountered in the process of estimating risks, the 1980 committee remarked, "If the estimates of risk from low doses of carcinogens are made with reasonable data and reasonable models, [there will be]
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From page 257... ...
Estimates of Exposure from Different Sources and Various Routes All sources of exposure must be considered when assessing risk or setting safety factors for estimating ADIs of chemicals in water, regardless of the biological end point under consideration. The population may be exposed to chemicals through air and food as well as through water.
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From page 258... ...
For regulatory purposes, an adequate description of the exposure-response relationship is more important. WATER For chemicals with a threshold dose, the ADI is based on animal toxicology data by applying a safety factor to a NOEL.
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From page 259... ...
(1984) proposed that absorption through the skin may contribute significantly to the total dose of volatile organic compounds received during normal daily use of contaminated water.
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, noted, "Even if only a small portion of the background incidence [of the toxic responses is associated with the same mechanistic process as the study chemical, linearity will tend to prevail at sufficiently low doses" (OSTP, 1985, p.
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From page 261... ...
) at the molecular targets, although under certain circumstances it can become linear at low doses (Hoer et al., 1983~.
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From page 262... ...
Part C of the figure shows the simplest behavior expected for an inducible oxidase, corresponding to the enzyme kinetics in part A, except that at a dose di, the cell responds to the inducer by producing more enzyme. As seen in part C, the applied dose to d*
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From page 263... ...
At the limit of low substrate concentration, the measured rate depends upon substrate-binding and enzyme-processing rates. An important experimental fact should be evident from these considerations: the information necessary to extrapolate from high to low doses cannot be obtained from observations of enzyme behavior at high doses, even if the formal relationship between dose and response is clearly understood.
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From page 264... ...
Although the dose response for dioxin activation or TPA modification of cell-cycle control may be linear at low applied doses, the events are complicated enough that the dose response may depart substantially from linearity under experimental conditions. As for DNA-binding carcinogens, experiments conducted at high doses may be affected by saturation and for that reason may not be extrapolated to low doses in a simple fashion.
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From page 265... ...
Some evidence suggests that humans are roughly as sensitive or in some cases more sensitive than experimental animals (California Department of Health Services, 1982; Crouch and Wilson, 1979; NRC, 1975, 19771. To predict carcinogenic risk to humans from data on animals, one should consider all the available data on the type of tumor produced, number of tumors, and time-to-tumor induction.
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From page 266... ...
The NOEL Volume 1 of Drinking Water and Health contained a detailed discussion of the relationship between classical toxicological testing and the extrapolation to low doses. In a classical testing protocol for a small sample, it is always possible to identify an applied dose do small enough that the elicited response cannot be distinguished from that detected in an unexposed control population.
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From page 267... ...
can be fit mathematically by many functional forms nearly equally. But calculations of probability of tumor occurrence at low doses based on those equations can vary widely.
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From page 268... ...
(1976) devised a mathematical approach for fitting a linear dose-response curve at low doses, which is consistent with a no-threshold model.
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From page 269... ...
The equation presented above formally corresponds to the multistage model of carcinogenesis, such as that of Armitage and Doll (19541. Threshold Models One of many alternative threshold models that have some heuristic, but less biological, appeal is the Weibull model: Prods = 1 —expE—(a + Admit, where Prod ~ is the lifetime probability of developing cancer when exposed at a dose rate, d; ax is the natural background incidence; ~ is a slope or potency coefficient (corresponding roughly to the qi in the multistage model)
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From page 270... ...
to the estimated risk at some low dose. When the only coefficient of consequence in the multistage model is A, and the shape parameter m of the Weibull model equals unity, the multistage and Weibull models give the same low-dose estimates of risk.
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From page 271... ...
In general, models that include thresholds for individuals predict a dose response that may become very flat at low doses. After being fit to highdose data, such a model may predict low-dose risk values substantially lower than those calculated from a linear or linearized multistage model (Swartz et al., 1982~.
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From page 272... ...
Trends in the data indicating biologically relevant increases in the incidence of adverse effects at low doses can be used to establish a LOEL if there is also an increased incidence of the same effects at high doses or if there is a statistically significant dose-response relationship. LOELs are most accurately identified under conditions where the response is minimal and the end point involves reversible developmental toxicity,
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From page 273... ...
Quantitative Assessment Some work is under way to develop a quantitative index for comparing developmental toxicity across species taking concurrent maternal toxicity into account (Fabro et al., 1982; Johnson, 19801. This approach derives from the perceived need to distinguish between compounds that are uniquely toxic to the embryo and those that induce developmental toxicity only at exposure levels that are also toxic to the mother.
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From page 274... ...
Existing models for quantitative risk assessment do not appear to be appropriate for data on developmental toxicity, for which there are probably threshold doses (Wilson, 19731. To establish safe levels for polychlorinated biphenyls, EPA (1983)
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From page 275... ...
The considerations discussed above suggest the following criteria for selecting safety factors for developmental toxicity data: · A minimum quality and quantity of data are required to perform a quantitative risk assessment. Thus, compounds not having a sufficient data base should only be qualitatively assessed for high, moderate, and low potential to cause developmental toxicity in humans, and should be assigned high, moderate, and low safety factors accordingly.
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From page 276... ...
Clinical experience with therapeutic substances has demonstrated that hundreds of pharmaceutical products can induce a variety of neurological and psychiatric disorders at prescribed therapeutic dose levels. By contrast, there are only 30 chemicals or industrial processes for which the International Agency for Research on Cancer (IARC)
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From page 277... ...
The NOEL and LOEL Information on general dose response for neurotoxicity in human populations exposed to environmental chemicals is extremely limited. For the one exception, lead, responses have been well characterized with reliable biological markers of toxicity that may be readily determined by assay of blood or other tissues.
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From page 278... ...
When there are no data on human populations, animal bioassay data are useful for estimating dose response for substances with toxic properties. Accurate models of human neurological disorders develop in most adult animals challenged with selected chemical substances administered at a suitable dose for an appropriate period.
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From page 279... ...
. At low doses of a given chemical, for example, the response may lie within the body's ability to maintain homeostasis so that no overt effect occurs.
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From page 280... ...
This knowledge could then be used to assess the uncertainty surrounding the extrapolation of animal data to determine the dose-response relationship in humans, and any safety factor (or confidence limit) could be adjusted accordingly.
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From page 281... ...
If resources are dedicated to experiments designed to identify a class of functions sufficient for modeling dose-response relationships for a group of neurotoxicants, benefits for future risk assessments for neurotoxins in the group will include the replacement of two major sources of uncertainty: (1) the problems involved in selecting a model for low-dose extrapolation will be lessened by the development of a procedure with measurable (via confidence limits, for example)
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From page 282... ...
Thus, forced cell proliferation may play a contributory, but not necessarily sufficient, role in the process of carcinogenesis. Mouse liver cells may be particularly sensitive to this type of action, which may explain the observation that mouse liver tumors have been induced with agents that did not produce tumors at other sites or in other rodent species and which apparently exhibit minimal or no genetic toxicity (Doull et al., 1983; Ward et al., 1979~.
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From page 283... ...
At present, we do not know He shapes of the low-dose curves or if Here is or is not a true threshold for an animal or human population for any carcinogen (Ehling et al., 1983~. There are no convincing data to support a nonlinear doseresponse curve or threshold at very low doses for any carcinogen (Hoer et al., 1983; Weinstein, 19831.
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From page 284... ...
However, the biochemistry also suggests that regulatory agencies should not be complacent about such a dose-response model, despite its simplicity and its apparent conservative approach to extrapolation to low doses. The dose response may be fundamentally nonlinear at low doses, and a linear extrapolation may underestimate risk for certain individuals, species, or tissues.
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From page 285... ...
The committee recommends that humans should be considered to be at least 50 times more sensitive than laboratory animals to agents causing welldefined developmental and reproductive toxicity. Substances that lead to developmental toxicity at levels lower than those causing maternal toxicity constitute a greater potential hazard than substances that cause developmental toxicity only at maternally toxic doses.
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From page 286... ...
Because quantitative dose-response models or even adequate measures of exposures do not exist, safety factors must be used. A NOEL or a LOEL must be identified and the observed doses divided by an appropriate safety factor.
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From page 287... ...
The approach is based on the argument that if no clinical manifestation of cholinesterase inhibition is observed unless cholinesterase levels are reduced by at least 20% or 30%, then the lower 95% confidence limit on the dose that produced such an inhibition could be looked upon as the acceptable, or maximum permissible, exposure level. To assess risk for neurotoxic end points, research must be conducted to develop measures of exposure, including biological markers; better laboratory techniques, including short-term tests for identifying neurotoxicants; and quantitative models for low-dose extrapolation, reflecting the different types of effects and species-to-species variability.
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From page 288... ...
1983. The Relevance of Mouse Liver Hepatoma to Human Carcinogenic Risk.
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From page 289... ...
1982. The relative teratogenic index and teratogenic potency: Proposed components of developmental toxicity risk assessment.
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From page 290... ...
Pp. 17-22 in IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: Chemicals, Industrial Processes and Industries Associated with Cancer in Humans.
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From page 291... ...
1975. Genetic expression of aryl hydrocarbon hydroxylase activity in the mouse.
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From page 292... ...
1984. Total Exposure Assessment Methodology (TEAM)
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From page 293... ...
1980. Chemical carcinogens.
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