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FORMALDEHYDE The Conquer Product Safety Commission's Risk Assessment for Formaldehyde William M. Stigliani A. BACKGROUNl) AMB CONTEXT 1 ~ Describe the chemical and i ts uses . Formaldehyde is a colorless, flammable gas with a strong, pungent odor. It can form explos ive :aixtures wi th air and oxygen. As an important industrial chemical of ma jor commercial use, formalde- byde is found throughout the environment . In outdoor air, it can originate from many sources such as incinerators, photochemical smog, and engine exhaust. Atmospheric levels of formaldehyde have been reported to range from less than 0.005 ppm to 0.06 ppm near industrial outlets or in areas of heavy smog. Corkers who smoke are exposed to additional levels of formaldehyde, since cigarette smoke contains an mucl, as 40 ppm of formaldehyde by volume. Thus, an individual who smokes a pack of cigarettes ~ day would inhale 0.38 ma, whereas occupational exposure to formaldehyde at 3 ppm could result in a daily intake of 29.0 ma. Production and Uses l Formaldehyde is usually manufactured by reacting methanol vapor and air over a catalyst (chemical initiator). This results in formaldehyde containing trace amounts of methanol and formic acid. Formaldehyde is sold mainly as an aqueous (water-based) solution called formalin, which is 37: to 50% formaldehyde by NOU: Thin case s Judy describes assessment procedures and summarizes issues and interpretations raised by others, but it is not intended to present independent pos itions or interpretations on either scienti fic or policy matters. The case has been reviewed by individuals outside the study project who are directly familiar with the federal analyses ant decisions described; however, responsibility for the paper rests with the author, and it does not necessarily reflect the judgment of the Committee on the Institutional Means for Assessment of Risks to Public Health or the National Research Council. It has not been subs jected to internal review procedures that apply to reports prepared by NRC committees. 1

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2 weight. It is also used in its solid form as paraformaldehyde and s-trioxane . The U. S. produced about 6.4 billion pounds of aqueous formaldehyde in 1978. Most of this quantity was used domestically. The U. S. consumption of formaldehyde by the year 1983 will likely exceed 7.5 billion pounds . Half of the formaldehyde produced is used to produce synthetic resins such as urea- and phenol-formaldebyde res ins . These resins are used primarily as adhesives when making particleboard, fibers board, and plywood. Urea-formaidehyde concentrates are also used in various coating processes, in paper products, and in malting foams for thermal insulation. The textile industry uses formal- dehyde for producing creaseproof, crushproof, flame resistant, and shrinkproof fabrics. Acetal resins, made from formaldehyde, are used to mold plastic parts for automobiles, home appliances, hard- ware, and garden and sporting equipment O Formaldehyde is used in some medicines because it modifies and reduces the toxicity of viruses, venoms, and irritating pollens. The use of formaldehyde in embalming fluids is now required by all s Pate laws. The widespread use of formaldehyde is due to its high reactivity, colorless nature, purity in commercial forms and low cost. In making other chemicals, it can link similar asked dis- similar molecules together. In the paper industry, formaldehyde and its derivatives impart wet strength, as well as shrink and grease resistance. Leather and fur can be tanned 'oy formalde- hyde. Formaldehyde is used in the photographic industry because it hardens and insolubilizes the gelatin surfaces of f ilm and papers. Release of Formaldehyde from Urea-Formaldebyde Foam Insulation (UFFI) . UFFI is a cellular plastic product used as a thermal insulation criteria ~ O The product is manufactured at the job ~ ite by feeding, generally, pressurized air along with two 1 iquid chemicals-~a urea- formaldehyde based (or urea-based) res in and a foaming agent-- through ~ foam equipment system. The product that resul, s from this reactive mixture has a starring cream~tike consistency and is usually pumped through relatively smal 1 holes into the wal Is of standing structures. After the llFFI is inside the wall, the insulation becomes firm or self-supporting. Formaldehyde that has not reacted with oilier chemicals after installation can eventually be released as formaldehyde gas. lithe likelihood of release of formaldehyde depends on factors such as temperature, humidity, foam formulation, architectural cons iderat ions, and ins tat let ion techniques .

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3 2. Describe how the question of risk was elevated to the agency agenda*. Irritation ant Sens it ization Initial focus of attention to the possible health problems of UFFI began in October 1976, when the Metropolitan Denver District Attorney's Consumer Office filed a petition, requesting the Conquer Product Safety Commission (CPSC) to develop a safety s tandard for certain types of home insulation products, including UFFI. The petition claimed that there is an unreasonable risk of injury or irritation associated with UFFI. Over the next three years, several thousand consumer complaints related to irritation and sensitivity from formaldehyde released from UFFI were filed with CPSC. After considering information compiled by staff, the Commission decided, in March 1919, to defer a decision on the part of the petition relating to UFFI and instructed the staff to evaluate additional information on possible means of addressing the alleged unreasonable risk of injury (44 FR 12080~. In addition, in May 1979, CPSC began the sponsorship of ~ National Academy of Sciences s tudy which "xamined the acute and s ens i- tization effects due to formaldehyde. The final report, issued in March 198D, stated that "an yet there is no evidence of a population threshold for the irritant effects of formaldehyde in humans. " lathe NAS committee also recommended that levels of formaldehyde be held at the "lowest practical concentration. " The latter suggestion may Cadre been influenced to some extent by a preliminary report to CPSC in October 1979 that formaldehyde caused cancer in rats. In November 1919, staff again briefed the Commission on the s talus o f information gathered concerning formaldehyde toxicity and UFFI. Follow~up investigation of some of the reported complaints indicated a range of severity of reported reactions varying from short-term discomfort to alleged chronic impairment, such as loss of visual acuity, reduction in lung function, and sensitization to other sources of formaldehyde. As a results of these briefings, the Commission decided to hold public hearings to obtain additional information on safety ant health problems associated with UFFI (44 FR 69578~. The Commission held public hearings in Portland, Oregon; Atlanta, Georgia; Minneapolis, Minnesota; and Hartford, Connecticut from December 19799 through February 1980. Consumers, industry representatives, state and local government officials, scientists, and others testified a t the hearings as to their experiences with UFFI and formaldehyde. Based on the information obtained in these hearings an well as the consumer complaints and medical and * This case study describes activities only through April 1982.

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4 scientific information obtained beforehand, the Commission9 on June TO, 1980, proposed a rule requiring manufacturers of UFFI to give specified performance and technical information to purchasers to alert them about the possible adverse health effects associated with the release of formaldehyde gas from the product after it is installed in residences (45 FR 39434~. Carcinogenic Risk In October 1979, representatives of the Formaldehyde Institute, an ir~dus try bate association, reported to CPSC the preliminary findings from a careinogenicity study sponsored by the Chemical Industry Institute for Toxicology (CTIT). This study showed that rats exposed to 15 ppm of formaldehyde developed squamous cet1 care inoma o f the nose . In January i9809 an Interagency Regulator Liaison Group (IRLG) task force including six pathologists visited CIIT to obtain additional information concerning the longs study and to verify the findings a In a report prepared in February 1980, the group concurred, in general, with the CIIT observations 9 diagnoses, and interpretations. As the ClIT experiment progressed and more data became available, the need for a full review of the potential health risks of cancer and other genetic diseases to toucans from chronic exposure to formaldehyde became evident. In April 1980, CPSC, in conjunction with the National Toxicology Program (NTP) formed the Formaldehyde Parcel, consisting of 16 federal scientists g charged -title reviewing and evaluating the avai late Le published and un- published information including the ongoing CIIT study. In its final report to CPSC in November 1980, the panel concluded that it would be "prudent to regard formaldehyde as posing a carcinogenic risk to 'numans. " Based in part on the findings of the Formaldehyde Panel 9 as well as on its determination of the irritating and sensitizing effects of formaldehyde g CPSC called for a proposed ban of UFFI in February 19810 The rule was made final in April 19632e 3. Under what statutes and agency ; urisdiction does ache chemical fall? What statutory tests governed the decision? . The ban of t3FFI falls under the jurisdiction of two possible CPSC statutes These are: Section ~ of the Consumer Product Safety Act (CPSA) and Section 2( q) ( 1) (B.) of the Federal Hazardous Substances Act (FHSA). The Commission chose to regulate under the CPSA for two reasons. First, under the MESA, the Commission lacked the authority to cover products installed in nonresidential applications such as schoolsO Secondly because of the complex and lengthy nature of the rulemaking proceeding that would be required under the FHSA, the Commission believed it would be in the public interest to regulate this product under the CPSA.

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5 under Section ~ of the CESA, there are two criteria that must be met before the Commission can issue a proposed ban. There are: (1) The consumer product is being, or will be, distributed in commerce and presents an unreasonable risk of injury; and (2) No feasible standard under the Act, including require- ments for warnings and instructions, would adequately protect ache public from the unreasonable risk of injury associated wi th the produc ~ . In CPSC ' s judgment, unreasonable risk was demonstrated by the irritant and sensitizing effects, and carcinogenic potential of formaldehyde . Lee Commiss ion examined the existing information concerning the feasibility of a standard and found that there was no feasible standard, including labeling, that would adequately protec t the pub kc . In its finding that it was not possible to establish a feasibility standard, CPSC denied ~ petition it received from the Formaldehyde Institute on April 16, 1981, which requested that the Commission issue a safety ~ tandard applicable to UFFI. 4. That was the decision schedule? Note any s tatutory or other action deadlines. October 19 76 Action: We Metropolitan Denver District Attorneys Consumer Of Eice filed a petition to CPSC, requesting the Commission to develop a safe ty standard for insulation products, including U.F.F. I. June 10, 1980 Action: CPSC issued a proposed rule to require manufacturers of UFFI to give information to prospective purchasers deco alert them to the possible adverse health effects associated with the release of formaldehyde gas from the product. Deadlines: Written comments to proposed rule to be submitted by . August L1, 1980. (compliance to begin six weeks after publication of final rule. November 20, 1980 Submiss ion of Formaldehyde Panel report to CPSC.

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6 February 5, 1981 Action: CESC issues a proposed rule to ban UFFI from residential, commercial, and public buildings in the U.S. CPS(: denies the leerier petition of October 19760 Deadl ines: Written cogent ~ to proposed rule to be submi tted by April 6, 19810 Oral presentation by interested parties concerning proposed rule to be presented Larch 20, 1981. April 10, 1981 Action: The Formaldehyde Institute fi led a petition to CPSC, requesting that the Cotillion issue a safety standard applicable to IJFFI. October 26, 1981 Completion of CPSC 9 S quantitative risk assessment. April 2, 19~82 Action: CPSC issues a rule to ban ~FFI from residences and schoo l ~ in the U ~ S a CPSC withdraws proposed rule of June 10, 19800 CPSO denies Fo~aidehyde Institute petition of April 10, 1981 Deadlines: The bass is effective on or after August to, 1982 or the day after the expiration of the 90 calendar day period of continuing session of Congress following promulgation of the ban, whichever date is later. B IDENTIFICATION OF HAZA R33 O (determining the presence or absence of potential tonic effects) 1. What health endpoints were evaluated? CPSC evaluated a wide range of potential adverse health ef fee ts front fo~aidehyde exposure. Acute effects, such as irrita~eton of the eyes9 nose and respiratory tract were examined9 as well as a wide variety of other effects such as drowsiness, nausea and headaches O

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? Sensitization of certain individuals due to fo~=aideh~e exposure was also addressed. CPSC was concerned about a small segment of the population which could be susceptible to severe reactions such as allergic dermititis and asthma. Finally, CPSC reviewed the potential of formaldehyde to ~nduc genetic disease. Ins effects on reproduction ant teratogenicity, mutagenicity and carcinogenicity were reviewed and evaluated, al though the main f ocus was on cancer. 2. What were the key data available for review? (What additional data were sought? ) e Prior to the release of preliminary data from the CITT study in November 1979, CPSC was almost exclusively concerned with potential acute effects and hypersensitivity caused by formal- deh~rde exposure. Over the course of about three years, the Commission had received over 2,000 consumer complaints of adverse health effects from the release of formaldehyde gas from UFFI. These complaints provided the CPSC witl, a readi ly available data base Deco examine the effects of interest. The Commission staff conducted follo~up investigations for over 200 of the complaints. In addition, CPSC asked the National Academy of Sciences (NAS) to conduct a study assessing the health effects of formaldehyde. A final report to the Commission was completed in March 198Q. Two other NAS studies Indoor Pollutants (1981) and Formaldehyde and Other Aldehydes (1981) were available for review and evalua- tion. After November 1979, CPSC was also concerned with the potential carcinogenic effect of formaldehyde. Review of the CIIT rat study began while it was still in progress. In January 1980, an I}lLO tack force was formed to verify the initial findings of CIIT and to ~ eek further informa ~ion. In a report prepared in February 1980, the group concurred in general with the CIIT observations. In April 1980, CPSC, in conjunction with the National Toxicology Program (NTP) formed the Formaldehyde Panel, consisting of 16 federal scientists, to continue Else review of the ongoing CIIT study. In addition, the Pane! was charged with evaluating all available published and nonpublished literature relating to other genotoxic endpoints. In November 1980, the Panel reported its conclusion to CPSC that it is prudent to regard formaldehyde as a human carcinogen. Four other groups of scientists in separate reports endorsed the opinion that formaldehyde should be viewed as if it were a h''m~n carcinogen. The first was a NIOSH Current Intelligence Bulletin. Another was a report based on a rat study conducted by scientists at New York University. In a letter sent to CPSC by Dr. A. Upton, professor and chairman of the New York University Medical Center, the NYU study was cited as providing 'decisive confirmation of the CIIT findings." The third was a report from a

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8 working group of the International Agency for Research OR Cancer (IARC) in October 1981. A fourth group, in a report to the American Cancer Society by the Environmental Cancer Information Unit, chaired by I. J. Selikof f and E. C . Hammond (February 1981), found that fo~aidebyde was an animal carcinogen and that human exposures should be reduced or eliminated There were some limited human studies on industry workers and morticians. CESC found these to be inconclusive regarding their ability to predict human carcinogenic effects. The same conclusion was drawn by a working group of IARC. 3. Ah_ ~ background? Available analytic resources? ) Irritation and Sensing ivi ty From the thousands of consumer complaints DISC rece ived, several hundred were singled out for followed investigation by CPSC. Part of the investigation consisted of answering a questionnaires Questions were designed by staff epidemiologists and chemists In addition, when the complainant was treated by a physician, the doctor was contacted to obtain further details. Also, a medical officer on the CPSC: staff reviewed the complaint file. She NAS analysis of health effects of formaldehyde, which was a key document in CPSC ' ~ a~se~:oent o ~ acute symptoms, was pert formed by 13 medical doctors and client. They had expertise in various areas including toxicology, epidemiology, and dermatology . Carcinogenic Effects The GREG tack force that made the preliminary evaluation of the CIIT study in January 1960 consisted of six pathologists representing CPSC9 NIGHS, DOE, EPA and NCI as well as other health scientists. The Formaldehyde Panel which made the final evaluso tion of the CllT study for CPSC consisted of sixteen scientists from various federal agencies including EPA, DOE, NCT, IDA, NIERS, NIOSE, NCTR, and OSHA. All of these had Ph.D.s, Sc.D.s or M.D.s, ant they represented expertise in the areas of carcinogenicity, metabolism, teratology and reproduction, epidemiology, mutagenicity, and risk analysis. The CPSC staff reviewing the Eormaldebyde data in both of these areas consisted of six Ph.D;s or DolteMe8. They hat backgrounds in carcinogenicity, metabolism, mutagenicity, risk analysis and toxicology, biochemistry and pathology a

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4. How was uncertainty described in reaching final interpreta- tions ? Were cruc ial as gumptions made exo1 icit? Irritation and Sensitivity lathe identification of the effects of irritation and hyper- sens itivity caused by formaldehyde exposure is quite certain. Controlled Bean studies where small numbers of young healthy adults were exposed to concentrations of for-`ualdebyde varying from 20 ppm to less than ~ pp~n for short periods provide the best evidence . Be NAS s tudy on health ef fects of formaldehyde (March 1980) discusses these and other relevan~c evidence in detail. There is some question as to whether studies on limited populations are applicable to the general population. The NAS study notes this limitation and enumerates the factors that might lead to a wide range of individual susceptibility; e.g., health status, genetic predisposition, age, pregnancy. Notwitlls~anding these factors, the NAS report does caution that "responses reported in controlled studies may occur at an increased rate in the general population, because of the interaction between formaldehyde and other irritants in the environment. " Finally, NAS states: "Some of the factors might decrease susceptibility; mos t may Increase fit. The poss ible exit fence of a threshold to irritation and hypersensitivity raises another point of uncertainty. The NAS study states, "As yet, there is no evidence of a population threshold for the irritant effects of formaldehyde in humans." The NAS leaves this question unresolved but advised maintaining "formaldehyde at the lowest practical concentration to minimize adverse effects on public health. " By the time NAS committee members wrote the final report, the preliminary results of the CIIT study were known. This new information probably affected their final recommendations. Care inogenici ty Since there are no definitive human studies to date for carcinogenic effects of formaldehyde, its potential carcino- genici ty in humans must be inferred from animal data. The lack of direct evidence was clearly stated by the Formaldehyde Panel. The Panel concluded that "definitive expe eiments exis t which demon- strate the mutagenicity and carcinogenicity of formaldehyde under laboratory conditions. " It further stated that "the data presently availab le do not permit a direct assessment 0 f the carcinogenicity of foe =aldehyde to man. " In reaching its final determination it stated: "it is the conclusion of the Panel that it is prudent to regard formalt~hyde as posing a carcinogenic risk to humans . "

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10 5. What qualitative factors affected the weighting of data? There mere two particular features of the CIIT study which the Formaldehyde Panel weighed before reaching its conclusions O One was the occurrence of a viral upper respiratory tract infection (sialotacyoadenitis) in the test animals at twelve months of exposure that lasted about one week. The virus event left open the possibility that the infection served as a co-carcinogenic effect contributing to the carcinoma response. Me other feature was that the rats developed severe irri tat ion in their nasal cavities due to formaldehyde exposure. his symptom raised the question of whether irritation effects In and of themselves could cause or contribute to a carcinogenic response. lye Formaldehyde Panel, in considering these two questions, did cot completely discount their importance, but concluded that it was unlikely that either could cause an experimental artifact. With regard Deco the viral infection, the Panel report stated that 'tua~al tumors had probably already formed at the time of the infection," thus casting doubt upon the possibility of ~ O co-care 1nogen~c response c The Panel addressed the question of irritation by stating they "found no evidence that the induc tion of irritation . O O is a sufficient condition for the carcinogenic activity of an agents" 6. What inference options were used in the Razard Identification step? Were they explicit and in accord with any general guidelines? Inference Options Used in Bazard Identification* (1) Degree of confirmation of positive results) significance . . . Of negative results: The Formaldehyde Panel reached its conch u lion b seed ~~ the positive CIIT rat study as well as other supporting evidenced T.nis evidence included: ~ a) Me NYtJ rat study of Laskin et al . that demonstrated a positive carcinogenic response from a different ~rain. (b) Me demonstrated genotoxicity of formaldehyde * The inference options cited here are drawn from Risk Assessment in the Federal Government.~Managing the Process, NAS ( 1983), ppO 29-30.

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11 (c ~ Suggestive evidence from species other than the rat and tissues other than the nasal epithelium; e.g., lesions interpreted to be carcinomas _ situ induced in the oral mucosa of rabbits. Me Panel reviewed the known data for hamsters, which apparently did not exhibit a carcinogenic response to formaldehyde. This negative result did not appear to influence the Panel's final conclusion, based on the positive animal s tudies . ** (2) Evidence of different metabolic pathways between animals and humans: The Formaldehyde Panel reviewed extensively the known ~- data about for~aldehyde metabolism but did not reach any conclusions about interspecies difference. lathe Panel did recommend as future research, that "the pharmacokinetics of formaldehyde and its interaction with target tissue should be studied in several animal species. " (3) Findings of tissue damage and other effects in the inter- ~ _ preta~ion of tumor data: The Formaldehyde Panel considered both the irritation effects and the cytotoxic of feces of formaldehyde. For irritation the Panel concluded that it was Inconceivable that the 'irritant' effect of formaldebyde...may contribute to some extent to the expression of its carcinogenic activity through a mechanism enhancing the promoting or tumor growth s t age of carcinogenesis. However, it must be added that our knowledge of this type of effect is still quite inadequate and not directly applicable to the reported carcinogenic ef fects of formaldehyde on the nasal mucosa. " Regarding cytotoxicity, the Panel noted that "most care inogens have significant cytotoxic effects. Therefore, formaldehyde is not an unusual case....In short, it is conceivable that the cytotoxic effects of fo'-=aldebyde may play a part of its overall carcinogenicity. " (4) Use of short-term test data: As noted above, the Formal- dehyde Panel used short-term tests demonstrating the genotoxic effects of formaldehyde an supportive evidence for the carcino- genic effects of formaldehyde. - ** 'rhe Panel did cite a (as yet unpublished) report indicating that formaldehyde might act an a tumor Enhancing agents' in the trachea of hams ters ~ but acknowledged the s tudy was 1 imited ~

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28 Variations Across Agencies Thus far, CPSG is the only agency to issue a final rule on formaldehyde use. IN based this decision on a risk assessment similar in many aspects to the EPA PRL-1 document which was criticized by Dr. Todhur`~er irt his February 1O5 1982 memo to Ms. Gorsuch. Even though the Todbunter memo does not specifically address the CPSC risk assessment 9 the issues raised therein do serve to highlight differences of interpretation of risk assess- ment data between CPSC and EPA. I ~ should be noted that the degree to which the two agencies differ increased significantly with the advent of the new administration at EPA in the spring of 1981 ~ see Question B. tO) . In specific terms, ])r. Todhunter states that, "Formaldehyde appears, therefore, to exhibit considerable species specificity with the rat, the most sensitive species so far tested. Concern that formaldehyde gas may induce tumors in humans should be tempered by this observation that formaldehyde c arc inogenicity appears to have a high degree of species specificity and a strong dependence on route of exposure." CPSC' s position is that the strong evidence of carcinogenicity in rats provides strong evidence of carcinogenicity in humans, especially in Light of the limitations o f the negative studies . Dr. Todbunter also argues that at low levels of exposure ( 1-2 ppm) formaldehyde may exhibit a toxicity much reduced from that predicted by the 1 ineasized model ut il ized by CPSC O He sites findings by CTIT to support thin argument. These are: (1) Reversibility of byperpLastic and metaplastic effects of formaldehyde at low exposure levels or short exposure t ides; (2) The presence of endogenous levels of formaldehyde in tissue ranging from 3-12 ppm; (3 ~ The absence of cytotoxie Of facts from formaldehyde levels at or below LoO ppm in air; (~) Evidence to sugges t that formaldehyde acts as a promoter. CPSC re jec ts the contention that Cheese arguments sugges t a nonlinear dose-response relationship at low dose, with greatly reduced risk at low levels of exposure. CPSC believes that formaldehyde is both an initiator and a promoter and that the reversibility and promotional aspect ~ points 1 and 4) do not argue against linearity at low doses especially when the property of initiation is CONS idered O CPSC further be lieves that tile absence of cytotoxic effects at loO ppm has not been at all demonstrated;

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29 and that, nevertheless, the concept of cy~cotoxicity is not relevant to the shape of the dose-re~ponse curve at low dose where initiation and promotion aspects of formaldehyde are still likely to be operating. Finally, CPSC believes the entogenous levels of 3012 ppm are also not derived from any existing data, and not relevant to the argument. CPSC notes that virtually all formal- dehyde in tissues is not free, but bound in a different chemical fore with entirely different chemical and biological properties. Another point of departure is interpretation of data on benign tu~OtSo Dr. Todbun~er does not directly address the question of benign tumor incidence in the formaldehyde rat study. He does address the topic generically when suggesting a definition for the term "serious. " (Part of the criteria for initiating Section 4( f) is the determination of "serious or widespread harm. " ~ The concept of "serious" harm would have more utility in the consideration of gene mutational events or birth defects than in the case of cancer since malignant neo- plasms in general are serious. Section 4( f) also draws a distinction between benign and malignant growths by use of the term "cancer" rallier than "tumors.'' The CPSC risk assessment did not consider benign tumors, mainly because the information regarding their inc idence was not reported to CPSC by CIIT at the time. CPSC 's risk assessment does state, however, that inclusion of benign tumor data would lead to an increas ed pred ic t ion o f ris k. Another point of difference regarding the interpretation of available epidemiologica1 data for formaldehyde. Dr. Todhunter states, ''There is a limited but suggestive epidemiological base which supports the notion that any human problem with formaldehyde carcinogenicity may be of low incidence or undetectable. In would not appear reasonable to say that a significant risk situation exists from this data." CPSC, after reviewing epidemiological evidence from written statements and oral presentations at public meetings concluded that none of the epidemiological s tudies to date were of ~uf ficient ~ tatistica1 sensitivity or qua L ity to draw any valid inferences regarding the magnitude of carcinogenic risk to humans. Scientists at NIOSH and a working group of [ARC concurred wi th the CPSC evaluation. The two agencies differ sharply on the levels of risk that should trigger concern. Dr. Todhunter states, "In terms of individual lifetime cancer risks, the various federal agencies do not tend tco regulate risks of ~ x 10-5 or lower and tend to be ambivalent about risks between 1 x 10-4 - 1 x 10-5. " He stakes further [hat, "In OPTS, the relative risk range of 1 x t`~~ to ~ x 10 or lower has been a low concern range in general." CESC's estimated risk for inhabitants of UFFI residences is 0.6 x 10 4 - 0.9 x 10-4. Also, in a proposed rule regarding chemical compounds in food-producing animals, F1)A

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30 suggested ~ risk of 1 x 10 6 over a lifetime as a trigger for regulatory action: "An increase in the level of risk to l in 10,000 might significantly increase human risk. It is difficult to choose between ~ in ~ million and ~ in 10,000 but the agency chose the more conservative number in the general interest of protecting Furman t~ealth,'t (FDA, 1919~. Finally, Dr. Tothunter states, "lathe results of the CIIT bioassay are, however, sufficient to establish that formaldehyde is a potential animal carcinogen with mode and degree of exposure quite important to the outcome." CPSC's opinion is that forTeal- dehyde is a definite animal carcinogen and should be a presumed human carcinogen. 3. To the extent there were issu~s/concerns about questions of silence 9 would tone outcome have been improved 'oy: - A better system of in-house scientific review? Review by an outside scientific organization? - Coherent federal guidelines on carcinogenic risk assessment? - Better agency guidelines on the performance of risk assessment? - Improved agency dec is ion procedures ? In the view of the author of this case study, many of the issues and concerns about the risk assessment of formaldehyde revolved around a complicated mix of risk assessment policy judgments and scientific judgments. On both s ides of the debate, there was often no clear distinction drawn between scientific and policy judgments O At the time the risk assessment was prepared, there were no uniform federal guidelines for carcinogenic risk assessment irt use. Such guidelines may'~ave been helpful in providing a scientif ic and policy framework to support the CPSC risk assessment, and in drawing sharper distinctions between scientific and policy judgments employed in risk assessments. Critics' comments may have focused on the generic scientific and policy issues raised in the guidelines. Furthermore, adherence to guidelines may have fostered a greater degree of explicitness in the use of inference options applied, and reduced the degree of inconsistency in interpretations among the agencies ~ i O e. ~ CPSC and EPA). The CPSC risk assessment may have !'enefitted from peer review by art independent science advisory panel. In general g this is good practice for all federal risk assessments.

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31 E. PERFORMANCE CONSIDERATIONS 1. Ab ility to obtain scientific information. CPSC staff felt that there was a problem obtaining pertinent data from CIIT as it was needed. Time-to-`c~or data and information on benign tumors was withheld until the release of the full final CTIT report in February 1982 (three months after the completion of the final CP5C formaldehyde risk assessments. Consequently, time-to-~or and benign tumor data were not cons idered in the final risk assessment in any quantitative fashion. Both pieces of information would have increased the risk had they been factored into the risk assessment. Other da ta, which could have weighted the evidence toward a reduced risk, was also withheld by CRT, although the results of these studies -were presented in part in November 1980 at a CIIT conference. One study dealt with evidence suggesting that fo.~al- debyde was not genotoxic. Another report was an epidemiology study which yielded negative results. In the view of CPSC, detai led documentation ~ f these resuL ts have, as ye c, not been released. One of the most important pi eces of scientific information is the pathology s [ides from the initial CIIT study. Six patholo- gist~ representing IRI`G there permitted to review the s rides in the middle of the study (January 1980~. No further review has been permitted since then, although CPSC and the IRLG Formaldehyde Task Group had requested such a reviews. CIIT maintains the position that, as a matter of policy, they lo no~c release data to any one party alone (i.e., the government); that the release of data has to be made public, and is nor privy to any one interes t group. 2. credibility of assessments, likelihood that interested parties would accept them as definitive. Hazard Ident if ic at ion The Formaldehyde Panel, IARC, NIOSH, the Sel ikof ~ and Hammond Committee Report to the American Cancer Society, the heads of NCI, NIEHS, and NCTR and three distinguished scientists at New York University Medical Center have all concurred that formaldehyde is a definite animal c arc inogen and should be cons idered to pose a human carcinogenic risk. Some interested parties could dispute these assertions, but it is likely that most would not.

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32 Quantification and Characterization of Risk to Humans Representatives of CIIT and the formal'1ebyde industry were highly critical of CPSC'~ quantitative risk assessment. As detailed in Question C.11, two main points of criticism focus on the choice ~ f the dose-response curve, and the quality of CPSC ' s exposure da t a . What was the extent of diversity of policy orientations . .. . represented within the assessment croup i tself . What was the decree to which interes t pressures would be exerted from outside the assessment group? What {:~5 the ~s~onsivenes s of the assessment to these diverse interests7 _ Both the hazard identification and the quantification of risk to huffs were performed solely by federal scientists. Hence, the extent of diversity of policy orientations was quite limited. It does not appear that there was any degree of integer t pressure exerted from outs ide the group. 4 What were the time ant resources necessary to comr~le to the . . . risk assessment? Hazard Identification Assessment The federal panel consisted o f 16 scientists working part-time actual percentage unknown) for 9 months . Characterization of Risk to Humans Seven CPSC staff persons worked full or part-time over two years collecting and reviewing data and reviewing comments. Me cancer risk assessment document (excluding the effort needed to obtain exposure data) required one person working full time for one year. 5. Responsiveness of assessment agenda to public concerns . . . interest group concerns, professional codeine, an~ e~er~euce of new scientific data. It appears that CPSC responded to public concerns regarding irritation and sensitivity effects with cautious but deliberate action, and it respond to the newly emerging information on formaldehyde as a Potts tial human carcinogen with swift, decisive action.

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33 As described in detail in Question A.2, the first public concerns voiced in October 1976 regarded irritation effects from formaldehyde release in UFFT residences. Wer the next couple of years, several thousand similar complaints were filed with CPSC. In order to obtain more detailed information on the full extent of human heal th concerns, CPSC asked the National Academy of Sciences, in May 1979, to prepare a comprehensive report. The report -~as completed in March 1980. Public hearings were 'nerd from December 1979 through February 1980 as industry, state and local government officials, scientists, and others testified on the question of UFFI ant formaldehyde release. As a result of all this activity, on June 10, 1980, CPSC issued ~ proposed rule '.~ch would require UFFI manufacturers to label their products giving specified performance and technical information to prospective purchasers. This rule was never made effective because in the view of CPSC the new emerging cancer data required more stringent rutemaking. lathe first preliminary data from the CIIT rat studies was presented to CPSC in October 1979. One month later, a briefing package prepared by s gaff was sent to the commits loners . In January 198~), an IRLG task force visited CIIT to verify the findings. In April 1980, the CPSC-requested Formal`lebyde Panel was formed to assess all current literature and make reco~enda- tions as to the severity of health ef facts. T'ne final report in November 1980 concluded that formaldehyde was a potential human carcinogen. In February 1981, CPSC published a proposed rule to ban UFFI. In October 1981, the final CPSC cancer risk assessment was completed. TO April 1982, CPSC published a final rule to ban IJFF1 . 6. Ability of the risk assessment to identify research needs. Interest in the possible harmful effects of formaldehyde generated an abundant 1 is tiny of research needs . The CPSC-sponsored National Academy of Sciences study on health effects o f Cormal- dehyde (March 1980 ~ identified twelve research needs including the areas of carcinogenicity, reproduction and teratogenic effects, sensitivity of population subgroups, pharmacokinetic studies, sources and fates of formaldehyde, and percutaneous penetration. The Formaldehyde Panel report identified research needs in teratology, animal reproduction, human reproduction, mutagenicity, carcinogenicity (pharmacokinetics, other routes of administration, neoplastic transformation of mammalian cells), epidemiologic research, and the ability of formaldehyde to interac t with other pal lutants .

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3/+ A major research effort has already begun with the goal of obtaining more definitive results from epidemiological data. Both NCI and NIOSH are examining data on large numbers of workers with a history of high formaldehyde exposure. ' OCR for page 1
3S 10. Mode and frequency of communication between assessors and regulators . Hazard Identification lye Formaldehyde Panel, in its appraisal of formaldehyde as a potential l`uman carcinogen, appeared to be acting entirely independent ty o f agency regulators . Characterize ion of Rick CPSC appears to 'nave organizational separation between the assessors and the regulators. lathe assessors, consisting of staff from the Directorate of Health Sciences, performed their function wi thou t apparent contac t wi th or guidance by the program team and the commissioners, who are the regulators.

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36 SOME: IMPORTANT REFERENCES CITEI) IN FORMALDEHYDE CASE STUDY Crump, K. S . and W. W. Watson. 1979. Global 1979. ~ fortran program to extrapolate dichotomous animal carcinogeraicity data to low doses. Dept. of Mathematics and Statistics, Louisiana Tech Univers ity. EPA (Environmen~at Protection Agency). 1976. Health risk and economic impact assessments of suspected carcinogens. Fed. Reg. 41: 21402. EPA ~ Environmental Protect ion Agency) . Of fice of Research and Developments Carcinogen Assessment Group. August 8, 1980. The Carcinogen Assessment Group's method for determining the unit risk estimate for air pollutants. External review copy prepared for Office of Air Quality Planning and Standards and Office of Air, Noise and Radiation. F})A (Food and Drug Administration). 1979. Chemical compounds in Eood~producing animals 9 criteria and procedures for evaluating assays for carcinogenic residues. Fed. R=go 44 17070. Food Safety Council, Final Report of Board of Trustees. June 1989 0 ~ Proposed Food Safety Evaluation Process. Gibson 9 J o E a December 15, 1981. Le t te r from Chemical Industry Ins t i tute ~ f Toxico logy (CIIT ~ to Consumer Produc ~ .Sa fe ty Commiss ion ~ CPSC ~ . Gibson, J. E. February 1;, 19820 Letter from Chemical Industry Ins t itute o f Toxico logy ~ C IIT ~ to Nancy S teort s, Cha irman, Cons ume r Product Safety ^ommiss ion (CPSC ~ . IARC (International Agency for Research on Cancer) 9 the Working Group O May 1982. Monograph on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Some Industrial Chemicals and Dye Stuffs: Formaldehyde, pp. 345-3890 TRLG (Interagency Regulatory Liaison Group), Work Group on Risk Assessment. 19790 Scientific bases for identification of potential carcinogens and estimation of risks. Fed a Reg 0 44:39858. Mantel, N. and M. A. Schneide~=an. 19750 Estimating "Safe" levels, a hazardous undertaking. Cancer Res. 35: 1379-138f'. NAS (National Academy of Sciences). March 1980. Formaldehyde: An Assessment of Its Realth Effects.

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37 NIOSH (National Institute for Occupational Safety and Health). Current Intelligence Bulleting #34. April 15, 1981. Formaldehyde: Evidence of Carcinogenicity . NYU (New York University). R. E. Albert, A. R. Sellak~ar, S. Laskin, M. Ruschner, N. Nelson and C. A. Snyder. 1982. Gaseous formaldehyde and hydrogen chloride induction of nasal c ancer in the rat. J. National Cane. Inst. 68 :597-602. OSIP (Office of Sc fence and Technology Po ticy) . D. R. Calkins, R a L a Dixon, c: . R. Gerber, 1) . Zarin, and G. S . Omenn. 1980 . Indentification, characterization, and control of potential human carcinogens: A framework for federal decis ionmaking. J . National Cane. Inst. 64 :169-176. Report of the Federal Panel on Formaldehyde. November 1980. Submitted to S. B. ICing, Chairman, U. S. Consumer Product Safety Commission. Also published February 1982, Environmental 'Realth Perspectives. 43: 139-168. Selikof f, I . ~ . and E. C. Hammond. February 25, 1981. Carcino- genicity of formaldehyde: final report to the American Cancer Society by the Environmental Cancer Info~!uat ion Unit . Environmental Sciences Laboratory, Mount Sinai School or Medicine. Todbunter, J. A. February 10, 1982. Review of data available to the administrator concerning formaldehyde and di(2-ethythexyl~phtha- late (~EHP). Memorandum to Anne Gorsuch, Administrator, En~rironmenta 1 Pro tee ~ ion Agency .

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