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39 NITRITE Catherine S ~ . Hi faire A. 8ACK&ROIJl~D AND CONTEXT 1. Describe the chemical and its uses. Nitrogen exists in nature in various forms one of which is nitrate. Nitrites are chemicals that form when living systems act upon nitrate salts, which are widely distributed in soil, plant s, and cancer, or upon n i trogen in o ther forms . Nitrite inhibits the growth of various microorganisms found in foods, including Clostridium botulinum. It also helps to maintain the typical reddish color of cured meats, inhibits the development of rancidity in meat and fish, and may contribute to the flavor of cured products. lathe addition of nitrite to meres has been permitted in the U. S. since 1925. It is currently added to meats and fish primarily as an antimicrobial. Approximately 25Z of all meats consumed by the U.S. population contain added nitrite. 2. Describe how the question of risk was elevated to the agency level . There are two aspects related to the risks of nitrite inge.s tion: (a) The contribution of nitrite to the formation of nitro- samines (a large group of chemicals over 90 percent of which are care inogens in animal ~ ~ . N_: This case study describes assessment procedures and summarizes issues and interpretations raised by others, but it is not intended to present independent positions or interpretations on either scientific or policy matters. The case has been reviewed by individuals outside the s tudy pro j ec t who are d i rec t ly f ami 1 far wi t h t he f ede ra 1 analyse s and 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 Realtl, or the National Research Council. It has not been sub- jec ted to internal review procedures the t app ly to report s prepared by NRC commi t tees .

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40 (b) The carcinogen/city of nitrite per se. Two agencies are involved in the regulation of the use of nitrite in cured meats--USDA and F0A. Interest in risks associated with nitro~amine formation stem from findings in the 1910s that vitro gamines were found in a number of foods. Earlier findings had also indicated that nitrosamines could form in the body fat lowing inges tion of nitrite. In 1970, the US~OA and FDA formed a group to coordinate research activities in tqnis area. In 1972, ache t?Sl)A was petitioned to ban or greatly reduce the use of nitrite. The petition was denied. Based on additional evidence of the presence of nitrosamines in bacon, the Secretary of Agriculture appointed an advisory Expert Panel on Nitrites ant Nitrosamines. In September 1974, the Panel provided a prel imaginary report which prompted USDA to propose several regulations that reduced the levels of nitrite permitted in various meat products ~ In 197S, the Panel issued its final report recommending levels of nitrite in a variety of products. USOA published a final regulation on the use of nitrite in bacons Further action on the rules proposed by USI)A in 1975 and the other reco~enda~cions of the Expert Panel were halted in mid-1978 by a report that nitrite Per se was carcinogenic in animal s. 3. under what statutes and agency jurisdiction does the chemical fall' What statutory tes ts governed the decision? lathe Federal Food, Drug, and Cosmetic Ace (2l U. S.C. 301 et seq. ~ (FI)&C Act), as amended on September 6, 1958, by the Food Additives Amendment (2l U.S.C. 348), requires FI)A to establish regulations prescrib ing the coadi tions under which a food additive may be safely used. The act defines a ''food additives as any substance which becomes or may be expected to become a component of foods either directly or indirectly or r.`hicl, may otherwise affect the characteristics of the food. Before a regulation can be established the additive must be shown to be safe and functional for its intended uses (i.e., it must accomplish the effect for which it is to be used--preser~ra~i~res must preserve). The act states, however, that no food adtiti,Je shall be deemed 3a fe if it is found to be carcinogenic ~ induce cancer) when ingested by man or animal or if it is found, after tests which evaluate the safety of food additives, to induce cancer in man or animal. Ibis provision is commonly known as the Delaney Clause. Under Chin provision if a substance is shown, based on scientific analysis, to induce cancer when fed to test animals, FDA cannot al low its uses

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41 In addition, if after its approval, a substance is found, by adequate scientific Stridence, to be carcinogenic, its '~se must be banned. I f the evidence is not sufficient to prove that the substance is carcinogenic out does raise substantial unresolved ques tions about its safety, the general safety clause o f the act (21 U.S.C. 348(c)~3~(A) ~ would require the banning of the subs tance . The requirements for revoking approval of a food additive are not as demanding under the general safety clause as under the Delaney Clause. Instead of proof that a substance causes cancer, FDA is required only to present new evidence raising a substantial unres o tved que s t ion about the s a fe ty ~ f an ap proved s ubs tance . FDA does not have the burden of proving that a substance causes cancer or that it is otherwise unsafe; FDA has only to present new evidence that raises a subs tantial safety question. lithe burden then is on the manufacturer to resolve the question by showing that the subs Lance is safe. The Food Additives Amendment exempts certain categories or' food ingredients from the definition of "food additive . " One such category includes those substances that have 'I prior sanctions. " substance has a prior sanction if its use in food was sanctioned or approved by FI)A or 'MISDO before September 6, t958, the effective date of the amendment. Such approvals were granted under provisions of the FDSC Act, the Poultry Products Inspection Act (21 U.S.C. 451 et seq. ), and the Federal Meat Inspection Act (2l U. S.C. Sol _ seq. ) . Because prior sanctioned substances are not covered by the definition of "food additive, " the provis ions of the Food Additives Amendment, including the Delaney Clause, do not apply to them. The three laws under which prior sanctions were granted provide, however, that the public is to be protected from adul- terated food products. They state that food is adulterated if "it bears or contains any poisonous or deleterious subs tance which may render it in jurious to health. " Thus, if competent scientif ic evidence demonstrates a reasonable possibility that some Consumers may be harmed by eating food containing a prior-sanctioned substance, the food is adulterated and cannot be introduced into the food supply. USDA is responsible for assuring that the Nation's meat and poultry supply is safe, wholesome, and properly labe led. While FDA has primary responsibility for approving the use of substances identified as food additives, US])A has the additional respon- sibility to determine that an FDA-approved additive may be used in meat and poultry products. This responsibility includes deter- mining that the approved additive w~11 serve a useful purpose and establishing a minimum amount of the additive necessary to achieve that purpose. USDA also restricts and monitors the use of approved additives to assure that requirements for safe use are met .

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42 40 Mat was the decision schedule? May 2, 1978 May 16, 1978 July ~ 1978 Augus ~ 28, 1978 October 18, 1978 [larch 3D, 1979 March 30, 1979 Top FDA and USDA of ficials are briefed on the s tudy showing that nitrite is carcinoo genie. (No written report submitted. ~ Special At Hoc Working Group begins review of s tudy and development of regulatory options . USI)A and FI)A seek Attorney General' s ruling on their plan to phase out nitrite and arrange for joint news con- [erence announcing they r decision concerning nitrite. FDA t s '"50-page paper" outs 1 ining agency ~ s dec i s ion to phase out nitrite is leaked. FDA-USDA news confe renc e ~ s cancel lied . Interagency Woricing Group (I.AWO) on nitrite meets. 2 pathologists on the IAW(; reported that patllolog~cal assessment of tumors in MIT study may be faulty. FDA contracted the UAREP, a nonprofit Consortium repre- senting pathology departments of 15 universities to review pathological s 1 ides of MIT ~ tuty . The Attorney General found that there was no legal basis for a ohaseout and . i ~ nitri te caus es cancer, the were to assure its removal from commerce agenc He s orderly

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43 March 30, 1979 Spring 1979 August 15, 1980 Augus t 1980 September 1980 December 1981 B. CHARACTERIZATION OF RISK TO HUMANS (Sections B & C were combined) 1 What health endpoints were evaluated? . Care inogenic i ty ~ as de tee ted in animal te s t s ~ Sec. of HEW and USDA hold press conference to announce intention to propose legis la- tion to prohibit FDA and USDA from banning before May 1, 1980 and to give F1)A and USDA the author) ty to phase out nitrite, if it is determined . . to Be carcinogenic ~ over a period of years ~ dependent upon the development 0 f alternative means of food preserve tion . A number of bills are intro- duced in Congress to prevent the agencies from banning or phasing out nitrite. UAREP report fail s to confirm carcinogenic) ty of ni tri te-- IAWG issues final report stating nitrite is not a car- c inogen . F1)A and 13SI)A announc e the t no ac ~ ion ski l l be ~ aken agai ns t nitrite . USDA - FDA under take jo int contrac t we th the NAS for review of health effects of nitrate, nitrite, and N-nitroso compounds. NAS releases final report confirming that nitrite per se is not a carcinogen but that it may contribute to formation of carcinogenic nitrosamines. .

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44 2. What were the key data available for review' study conducted for the FDA by Or. Paul Newberne, a senior pathologic t at MIT, which showed that nitrite caused a statistically significant increase in the number of lymphoid tumors in rats. In tale large lifetime s tudy conducted for the Food and Drug Administration (FBA), sodium nitrite was administered to groups of approximately 68 male and 68 female Sprague-0awley rats under a variety of conditions. Groups ~ to 5 received 0, 250, 500, 1,000 or 2,000 mg/Icg sodium nitrite in the diet, and groups 6 and 7 received ~ ,000 or 2,000 mg/titer in drinking water. For these groups, an agar-based semisynthetic diet was used. For groups 9 to Il. a commercial chow diet was substituted, and sodium nitrite concentrations of 0, 1, 000 or 2, 000 mg/Icg diet were fed to the animals. Groups 13 and 14 were given a refined casein diet containing nitrite at O or 1,000 mg/Icg, while another two groups, 15 and 16, were fed the original semisynthet~c diet containing nitrite at ~ or I, 000 mg/kg. Each of the latter two groups contained only 34 animals -the dams that supplied the pups for groups t and 4 0 Groups 17 and 18 were al so f ed the s emisynthe tic diet containing nitrite at O or 1,000 mg/kg. Groups 1 through 16 were exposed prenatally, simile groups 17 and 18 were exposed at 21 days. Groups 3 and 12 served as positive controls and received urethane (2,000 mg/liter) in drinking water or in the semi- ~ynthetic diet, respectively. The rats survived the sodium nitrite regimens well, the only adverse effects being a loss of weight in groups receiving 2,000 mg/kg in their died and, to a lesser extent, in groups receiving 2,000 mg/liter in drinking water. Histopathologic assessment of the tissues indicated that by considering all the groups receiving sodium nitrite together, there was a statistically significant excess of lymphoid tumors ~ p ~ 0 . 01, based on ch i-s quare analys i s ~ . ~ is was re f lee ted especially in the groups receiving sodium ni trite in drinking water, where the excess of lymphoid tumo. s was statistically significant, but the results were not significant in the other groups treated with sodium nitrite. In addition to malignant tumors of the lymphat ic system, an alteration referred to as immunoblastic cell proliferation was observed in the spleen and, occasionally, in the lymph nodes of some members of all groups except the positive controls (groups of 8 and 12 ~ . The incidence of this abnormal i ty in nitrite-created animals, however, was greater (11.2%) than in the untreated animals (7%) . T.ne disease in humans, which is histologically similar to that observed in rats, is cons ideret by some to develop into tymphc'ma; others consider it not to be preneoplastic. These results were taken as an indication that nitrite is an enhancer or promoter of carc~nogenes is in rats.

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45 3. To performed the initial analysis ? 'The FDA commissioner appointed a special ~ntra-agency Ad Hoc Working Group to review the data and to make recormnendationse The Chief Counsel was responsible for overall development of the regulatory policy and the Acting Director, Bureau of Foods was responsible for directing the scientific review of the study. The other members of the Ad Hoc Working Group were the Commissioner, Deputy Commi so loner, Execut ive Ass is tent to the Commiss toner, Associate Director of Regulatory Affairs, Director of Health Affairs, and two staff scientists from the Bureau of Foods . 4. To what extent were the resut ts presented quantitatively? What factors influenced the degree of quantification? The data from the MIT study were used to estimate leukemia-like cancer risks to humans (Table I). 5. Row was uncertainty described in reaching the final inter- pretations? Were crucial assumptions made explicit? Assumptions that had to be made were listed: (a) Cat humans consume t/4 of the amount of nitrite initially added to cured products. (b ~ Chat humans and rats are equally sens itive to the cancer- causing effect of nitrite. ~ c ~ That there is a linear relationship between the incidence of cancer resulting from the doses ingested by the rats and that resulting froro the doses to which the average American is exposed. (d) That the risk of cancer from nitrite is evenly spread over the American population. 6. How were qualitative factors dealt with? A discussion of the validity of animal tests was included in a document (the "50-page paper'') describing the basis for FDA's and USDA's action regarding nitrite. This discussion did not empha- size the uncertainty of extrapolating from animals to man but instead served to refute arguments that have been made against this use of animal tests.

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46 TABI`E I: ESTIMATED LIFETIME CANCER RISK FROM NITRITE* ( From the "50-page paper" ) Based on I no idence In Tes t Ra ts o f Dietary Source of Nitrite All sourc es Cured meats (200 ppm nitrite) o LYmohomas . . 1/ 3450-1/2040 (209 - 4O9) Lymphomas + I~unoblastic Ce 11 prol if erat ion 1/1560-1/794 (6.4 - 12.6) 1.6 oz~day 1/16,7001/9090 1/7L40-1/3700 (0.6 - 10 t) (lo4 - 247) 8 oz/day 1/3230~1/1890 (6.8 - 13.5) (40 ppm nitrite) 1.6 oz/day 1/100,000-1/50,000 1/33, 300-1/20, 000 (0. 1 - 0.2) (0.3 - 0.5) oz/day 1/ 16, 700-1/943 I/ 7140-1/3700 (0.6 - 1006) (104 - 2.7) *lathe two risk estimates in pacts case are based on: (1) the amount of nitrite added to the rats' food or water; and (2) the average amount of nitrite to which the rats were actually exposed at each dose level. The numbers in parentheses are the estimated lifetime cancer risks per 10,000 population.

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47 Other key qualitative factors were neglected, including the basis for concluding that the tissue changes in the rat spleen were actually related to leukemias. Ibis problem awaited scientific critique and eventually led to the refutation of the FDA conclusion. Other factors were the absence of a dose-response ant a charge that the different groups o f tes ~ animals became mixed during the course of the experiment . 7. Mat qualitative factors affected the weighting of data? Were such criteria explicit and in accord with any general guide- 1 ines ? - The only qualitative factors discussed in this analysis were: ~ a) The acceptance of animal tee ts conducted at high doses (this is consistent with [RLG guidelines.) (b) The assumption that low dose effects are linearly related to }ligh dose effects, i.e., effects are directly proportional to dose even at lower doses. Allis is consistent with IRLO guidel ines . ~ 8. Describe any internal, internal advisory, and external scientific review of the initial analysis. that, if any, cri ticism was incurred? Apparently, there was no internal or external peer review of the ini tial analys is prior to ache Commiss loner informing the Secretary of HEW of the plan to phase out nitrite. In August 197S, an Interagency Working Group composed of scientists from FDA, USDA, and NIH was convened to review the scientific data of the MIT study. At the same time, the study results were sent to outside reviewers. The following criticisms were made: (a) The method of showing statistical significance (combining all treated animals in one group) was improper. (b) The control groups had an unusually high incidence of lyTephomas. c ~ Dose-response was no t c [early demons tra ted . (d) Additional studies in another strain of rat and another species should be conducted before reaching a conclusion.

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48 ~ e) The possibility that the tumors were caused by nitro samines could not be ruled out. (f) The accuracy of the pathology diagnoses was questioned by IAWG pa~hologis ts who reviewed some o f the tissue ~ rides . 9. How were the issues raised in the reviews ac~o~mnodated? . . . ~ The ma jar issue was the ques tion of pathological diagnoses ~ Mile Interagency Working Group on Nitrite Research reviewed a sample of histological slides and decided that there was sufficient difference of opinion in the diagnoses to warrant a further evaluation of the histopatl?ological findings. The Uni~rersi ties Associated for Research and Education in Pathology (UAREP), a nonprofit consortium of 15 universities organized ho carry out education and research activities in pathology, was selected by the FDA to review the slides. A Joint Committee of Experts, which was established by the UAREP to perform this review, diagnosed fewer Amphoras than had criminal ly been reported . The dispari ty be tween the two series of diagnoses involved the differentiation of lymphomas from extramedul lary kematopoiesis, plasmacytosis, or histiocytic sarcoma. Further- more, the committee was unable to confirm the diagnosis of immunoblss~ic byperplasiaO In i ts f inal report to the FOA, the Government Interagency Working Group summarized its assessment of the 1JAREP committee 's findings as follows: I've major result of the histopathology review was that most of the lymphoma diagnoses originally reported were not confirmed A relatively high incidence of lymphomas had been reported by Or. Newberne, [the scientist who conducted the original study] with a significantly in- creased incidence in the total combined treated groups as compared to combined controls. Me UAREP pathologists, on the other hand, diagnosed very few les ions as lympho~na, with a resulting reduction of incidence to approximately 1: among treated and contra 1 group s . Thi s ra te 0 f 1yrephoma incidence is similar to that usual ly seen spontaneous ly in Sprague-Dawley rats. UAREP pathologic ts did report a greater than 1: incidence of other types of tumors, including his tiocytic sarcomas, angiosarcomas, liver neoplasms, ear duct tumors, pancre- atic tumors ~ pituitary tumor, and mammary tumors. However, after statistical analysis and careful review by the IAWG, no demonstration could be found that the increased incidences of these tumors were induced by the inges tion of sodium nitrite.

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49 10. What other issues arose concerning scientif ic data and their use? Briefly describe d issenting opinion. See question 8 11. Is the substance subject to past or possible future regulatory actions in other programs ? If so, did the program office coordinate with other agencies or programs? a_ The use of nitrite, especially in terms of the amounts permitted in various products, has been regulated in the past (and is subject to future regulation) by the USDA. In the case of the planned phaseout of nitrite, FDA informed USDA of its activities-- the original announcement was to 'nave been made jointly by the Secretaries o f HEW ant {JSDA. C . INTO Rl?RETArl019 1. What role did risk assessment have in the f inal agency docu- ment where standards were established ( proposed) to control the che~nica 1? (a) Risk assessment was used to show the reduction in risk associated with a decrease in the amount of nitrite added to bacon from 120 ppm to 40 ppm. (b) Risk assessment was not used to compare risks from cancer with risks from botulism ~ if nitrite were eliminated) . The Ad Hoc Working Group felt the data were insufficient to derive such an es timate . It seems clear that the risk assessment was performed after the decision to regulate had been made. Historically, both the Commissioner of FDA and the Assistant Secretary of Agriculture at that time believed that nitrite should be reduced based on the nitrosamine potential. The latter individual had been frustrated by the seeming requirement that nitrite itself be care, nogenic not just a precursor to nitro~amines in order to remove it from the food supply. Thus, when the tata apparent ly indicating a direct carcinogenic effect emerged, the premise upon which nitrite could be removed from food was obtained and led immediately to the development o f regulatory strategies .

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50 2. Were there variations in the assumptions used? Were these Two risk assessments have been performed by FDA: ~ a) in the original Working Group Document (described in preceding ques ~ ions ~ . (b) in a subsequent report of the Nitrite Bask Force (formed within the Bureau of Foods of F1)A). ways . The second assessment differed from the first in the following ~ a) Newberne reprised his own data af ter the original risk assessment was done, Cue second assessment uses the revised data. (b) Equal sensitivity to nitrite between rats and humans was assumed on a mg/kg-body-we ight teas is rather than a cone ent ra t ion-~n- theoso 1 id-die t teas is . (c) In the earlier assessment, it was assumed that 1 ppm of nitrite in water ~ 1 ppm nitrite in sol id diet . The second assessment assumes 1 ppm in water = 2 ppm in dice. (~) Di fferent estimates of daily nitrite intake for humans were used. The second estimate was approximately 9Z of the original est imate. (~e NAS also did a risk estimate for cancer risks from nitride; however their estimate of carcinogenic risk was based on ache con~cribution of nitrite to the formation of nitrosarQines--not as a direct result of exposure to nitrite. ~ 3. To the extent that there were issues/concerns about Questions . of science, would the outcome have been improved by coherent federal guidelines on carcinogenic ri sk assessment? Yes. Despite the fact that the major Elaw in the inter- pretation of the study stemmed from differences in pathologic diagnoses that cannot be addressed by inference guidelines, there were many other scientific issues that were not appropriately cons idered in the initial assessment of risks done by IDA. Adherence to comprehensive guidelines would have required that these issues by looked at more carefully and be addressed in the risk assessment documents Such consideration may have led to a more intense peer review of the study and its interpretation by FDA .

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51 In this case, peer review of agency decisions and the science underlying the decisions Is probably more important than the use of risk assessment guidelines. Vigorous peer review did not enter into the process until the decision to regulate had already been made. Normal methods of FDA review were not followed for reasons that, at the time, appeared justifiable. In my opinion, it is 1 ilcely that the normal peer review procedure would have revealed the fatal flaws in the MIT data since the normal procedure* would have called for the formation of an IAWG and it was in the Working Group that the questions about the strides pathology diagnoses were first raised. In addition, more stringent agency oversight of projects, such as the Newberne Study, 'which have major policy implications, eight have arrested the situation even earlier in the proces s . PERFORMANCE CONST DERATIONS 1 Ability to obtain relevant scientific information . FDA contracted for this study. One way to approach this question is to focus on the importance of quality control and peer review/ oversight of FI)A-sponsored research. A GAO report was highly critical of FDA monitoring of the MIT study. Also, GAO recom- mended that research guidelines should be developed for design, data-recording and reporting, and statistical evaluation for carcinogenicity assays. Thus, FDA's ability to get reliable information in this case was dependent on its own foresight in planning the study and its co~nit,nent to ensuring that the experiment was conducted and interpreted properly. A major consideration leadin. to inadequate oversight was the high regard FDA scientists had for Dr. Newberne and his institution--MIT. As it turns out, a major portion of his pathological diagnoses was done by ~ tudents no t Dr . Newberne himsel f . US])A and FDA do not have a formal written pa licy for evaluating sc ientific information concerning the safety of food additives. There is an informal review process that is supposed to identify the strengths and weaknesses of the data and the possible regulatory alternatives. Bureau of Foods is responsible for scientific evalua- tion. If cancer is involved, the Division of Toxicology begins the review. The study is then forwarded to the Cancer Assessment Committee. If the Committee members feel that a substance has major scientific, economic, and regulatory significance, they will recom- mend formation of an interagency working group (IAWG) to evaluate scientific meri t.

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52 SO Credibility of assessments. Assessments were done by four different groups: The Ad R.oc Working Group, a Bureau of Foods Task Force, the Interagency rWorlcing Group, and the NAS. The credibility of the initial assessment was low. Scientists within the agency who normally review such data and who were not involved in the review of ni trite felt uncomfortable with the caliber of individuals reviewing the study. Subsequent review of the study revealed many flaws in tie data, casting further doubt on the conclusions drawn in the original assessment. The credibility of the second review was not a major issue as this was an internal document looking at the broader issues of nitrosamine formation as well as nitrite carcinogenicity. The final results of the TANG deliberations were released two years after its review began. These results were supported by an independent pathology review. Thus, it had more credibility than the first assessment. The findings of the NAS Committee on Nitrite have been largely accepted. 3. What was the extent of diversity of policy orientations within the assessment group? Outside pressures? Impact of pressures ? Since the Ad Hoc Working Group was composed entirely of FDA staff chosen by the Commissioner, it seems reasonable to assume that similar "pot icy orientation" was shared 'oy the members of this group. The Working Group ~ s deliberations were not conducted in an open, public manner. Instead, their proceedings were kept secret, even from other FDA personnel, because of the importance of the issue and the fear of premature release of information. Thus, outside input into the process was minimal and specie 1 interest pressures would not blare come into p lay. FIowever9 the Working Group was very much aware of the iTnplications of their decision which would affect a $12-bilLion/yr industry and this fact, along with the knowledge that nitrite protects against another risk-- botulism, most certainly affected the final approach suggested by the Task Force. 4. What were the time and resources necessary to complete the risk assessment? The fire t assessment took two months . Me second assessment by the IAWG took from Angus t 1978 to March 1979 to comple te initial review and arrange for outside pathology review. The results of that review were available in August t980 and a final report of IAWG was issued August 15 $ 1980. Cost of this review was approximately $900,000. The total time required for the second assessment was two years.

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53 lithe NAS report took IB months to complete and cos t approxi mately $500, 000. ;. Responsiveness of the assessment agenda to public concerns, interest group concerns, professional concerns, and emergence of new ~ c ientific info. ma tion. The decision to form an Ad Hoc Forking Group actually stemmed from the Commissioner' s prey: ous experience with the proposed saccharin ban, i. e., it reflected an agency awareness o f public concerns and the importance to consider alternative regulatory actions. The subsequent appointment of an Interagency Working Group resulted from questions raised by F1)A scien~is ts concerning the carcino- genicity data used to support the agency's regulatory position. 6. Ability of the risk assessment to identify research needs. Although the director of the Bureau of Foods presented recommenda- tions for additional research to clarify some o f the uncer~cainties in Newberne's data, the FDA commissioner's judgment was that no additional research was necessary. 'Thus, the first assessment does not identify areas where further research might clarify the issue. Later assessments did addres s Allis issue to varying degrees; for example, the assessment done by the NAS does address this issue rather extensively. 7. Extent to which risk assessment impeded or fac ilitated regulation. This is ~ confusing question because regulation was inappropriate in this cane. So, if the question is reworded to "impeded or facilitated making the most correct (or defensible) policy decision'' I would answer that the assessment done by the Ad Hoc Working Group did not result in the appropriate policy decision while the assessment done by the IAWG did. The recently released NAS review of nitrite would concur wi th this cone fusion. S. Were related risk assessments consistent? ., No. (This question was addressed earlier. ~ AsseserQents done by different groups led to different qualitative and quantitative conclusions. That is, the Ad Hoc Working Group concluded that nitrite was a carcinogen, as did the Bureau of Foods Task Force; however, the risk estimates o f these two groups differed by tenfold. she IAN concluded that nitrite was not carcinogenic, as did the NAS Committee on Nitrites.

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54 9. tfas there a distinction between the weights given to science and policy considerations? Some observers of the nitri te decision would sugges t that policy considerations were weighted more heavily than scientific con: siderations in the initial as se~sment done by the Ad Hoc Forking Group. Certainly, the makeup of the Group would indicate that the "policy-~ypes" out numbered (and outranked) the scientists inc. luded i n the group . 100 Mode and frequency of commun~cat ion between assessors and regulators. In the At bloc Working Group, the assessors and the regulators were separated into two subgroups. The working group met frequently during the two-mon~h period. In addition, the chief counsel did review and convent on the scientific report, suggesting that there was some interplay between two subgroups.