From Microbes to Men: The New Toxic Substances Control Act and Bacterial Mutagenicity/Carcinogenicity Tests

On October 11, 1976, five years after initial introduction of federal legislation to regulate toxic substances, President Ford signed into law the Toxic Substances Control Act (TSCA).¹ Although the regulatory scheme established by the TSCA is in some respects cumbersome and fragmented, due in large part to the close balance of opposing forces in the 94th Congress, the Act is probably the most significant piece of environmental legislation to be enacted in the last two years. Moreover, recent advances in the science of toxicology give substantial promise of easing the cumbersome and costly aspects of regulation under the TSCA.

The TSCA subjects a broad range of consumer, commerical and industrial chemicals and mixtures to direct (and, for new compounds, anticipatory) federal regulation for the first time. In general terms, it fills the regulatory gap between pesticides, already subject to pre-market screening by the Environmental Protection Agency (EPA), and food, drug and cosmetic chemicals, which fall under the jurisdiction of the Food and Drug Administration (FDA). The Toxics Act subjects to commercial restrictions any chemical found unreasonably hazardous by the Administrator of EPA.

Substantive Regulatory Standards

The standards for regulatory action are precautionary. Regulation is triggered by risks of harm, not actual damage. Precise regulatory norms vary in stringency according to the intensity and duration of regulatory impact on importers, manufacturers, processors, or distributors, as the case may be. Thus, where the Administrator finds that any aspect of commerce² in a chemical "may" pose an unreasonable risk to health or the environment, and if there is insufficient data to evaluate it rationally, he must require its proponent to test it.³ On the other hand, should the Administrator conclude that commerce in a chemical "presents" an unreasonable risk, he may subject such commerce to restrictions ranging from simple labeling requirements to total prohibition.⁴ Finally, should a chemical appear imminently hazardous," it is subject to judicial seizure or recall, or other stringent protective measures on application by the Administrator.⁵

The Administrator's powers with respect to new chemicals are more comprehensive. Persons planning to introduce new chemicals on the market must, beginning in late 1977, notify EPA at least 90 days in advance of intended marketing.⁶ The notice must give the chemical's properties, structure, intended use, expected production levels, and the results of any previously-imposed testing obligation. If, more typically, the chemical is untested and is expected to have substantial environmental or human exposure, or if the Administrator believes it "may" pose a risk of harm, he may require testing. If the pre-market notification period (which EPA may extend up to an additional 90 days for cause) will expire before completion of testing, EPA may propose to extend the marketing ban pending completion of testing. If the new chemical's proponent objects, EPA must seek an injunction to prevent marketing. The district court is, however, not to use normal equitable standards, but rather to apply the same standard as the Administrator: potential risk or large-scale substance dissemination and human or environmental exposure.⁷ In the event the Administrator concludes that a new chemical presents unreasonable risks of injury, he may commence proceedins to regulate it under the provisions of § 6.⁸

Information Concerning Chemicals

Central to effective operation of the TSCA is adequate dissemination of information concerning chemicals and their effects of the EPA Administrator and members of the public. Several provisions of the Act bear on information supply. First, as noted, manufacturers and processors must supply basic information to the Administrator concerning new chemicals at least 90 days before initial marketing. The Administrator in turn must summarize this data in the Federal Register.⁹ A more general requirement¹⁰ is that the Administrator promulgate rules under which those who deal in chemicals must keep records and make reports concerning chemicals' names, identity and structure, categories of use, amounts manufactured or processed, byproducts, [6 ELR 10249] occupational exposures, and environmental and health effects (small manufacturers are to be exempted from some of these duties). In addition, records of significant adverse effects on health or the environment must be retained and lists and copies of health and safety studies performed on chemicals must be supplied to the Administrator.

Section 10 directs the Administrator, in cooperation with the Secretary of Health, Education and Welfare and heads of other federal agencies, to conduct such "research, development and monitoring as is necessary to carry out the purposes of this Act" This includes establishment and operation of a data-retrieval system for use throughout the federal government; coordination of research into development of "rapid, reliable and economical screening techniques for carcinogenic, mutagenic, teratogenic, and ecological effects of chemical substances and mixtures;¹¹ establishment of research into monitoring techniques and instruments; and training of laboratory and technical personnel in contemporary toxicological research techniques.

Public release of information obtained by the Administrator concerning chemicals and their effects is subject to § 14, which makes it a crime to release material exempt from disclosure under the "trade secret" exemption of the Freedom of Information Act.¹² Such Information must, however, be released to agents of the government in connection with official duties related to health or environment, to contractors doing essential studies, whenever deemed necessary to protect against the risks of chemicals, and when relevant to any proceeding under the Act. Moreover, § 14 does not bar release of data from health and safety studies except for proprietary details and does not authorize withholding information from Congress.

Regulatory Procedure and Judicial Review

The most cumbersome aspect of the TSCA is the complex procedure required before the Administrator may take regulatory action of almost any kind. Except for the flat statutory requirement of 90-days notice for intended marketing of new chemicals, every regulatory requirement must be the product of informal rulemaking under the Administrative Procedure Act,¹³ fortified by opportunity for cross-examination and preparation of a verbatim transcript.¹⁴ Thus, for example, testing must be imposed by rule, as must marketing restrictions or bans under § 6; recordkeeping and report filing obligations; and designation of new uses of existing chemicals under § 5. The last is the least workable provision, for it means that time-consuming rulemaking must precede designation of new uses, while premarket notification of new uses cannot be required until the rules designating them are promulgated.

In order to ease the Administrator's regulatory burden, § 26(c) authorizes him to take regulatory action with respect to categories of chemical substances or mixtures as well as single substances. A "category" is defined as

a group of chemical substances [or mixtures] the members of which are similar in molecular structure, in physical, chemical, or biological properties, in use, or in mode of entrance into the human body or into the environment, or the members of which are in some other way suitable for classification as such for purposes of this Act….

The conferees made explicit their expectation that "the Administrator will find the authority to categorize especially helpful in promulgating rules under section 5(a)(2) concerning what constitutes significant new use of chemical substances."¹⁵ Independent of new uses, the Administrator's authority to act with respect to categories strengthens his hand in promulgating rules. Rather than cover a single substance, a testing rule or a regulatory rule may be couched in broad enough terms to cover many substances.

Contributing to the TSCA's regulatory clumsiness is the scope and standard of judicial review of EPA's rules. Pre-enforcement review of any rule may be had upon the petition to a court of appeals within 60 days of promulgation.¹⁶ Review is governed generally by chapter 7 of the Administrative Procedure Act (APA), except that the TSCA imposes the substantial evidence test to the administrative record as a whole. The record consists of the rule, the Administrator's underlying findings concerning risk, the transcript of oral proceedings, written submissions of interested parties, and any other information deemed relevant by the Administrator and identified in the Federal Register prior to promulgation of the rule.

Congress' insistence on the substantial evidence test may pose problems, for it seems inconsistent with the risk assessment on which TSCA rule making is to be based. But the last sentence of § 19(b) indicates that "evidence" is not to be construed in the usual empirical sense: "The term 'evidence' as used in clause (i) means any matter in the rulemaking record." Moreover, by virtue of the premarket screening requirement, the Administrator must balance risks of injury from a new chemical against equally uncertain projections of benefits (e.g., production, sales, profits and jobs). Thus, the relevant "evidence" will be of roughly the same speculative character on both sides. In case of judicial review, this should minimize the likelihood of a judicial bias in favor of requiring "concrete facts."

Where the Administrator allegedly fails to take a non-discretionary action, or where any person is claimed to be in violation of the statute or a rule, a citizen's civil action will lie in federal district court.¹⁸ Sixty days' advance notice is required, except if the suit challenges the Administrator's alleged failure to seek [6 ELR 10250] judicial relief against an imminent hazard under § 7, in which case 10 days' notice suffices. Legal costs and attorneys' and witness' fees may be awarded by the court in appropriate cases.

Initiation of rulemaking looking toward regulatory rules is generally not mandatory. Nevertheless, interested persons may petition the Administrator for issuance (or amendment or repeal) of rules or orders.¹⁹ The Administrator must respond to such a petition within 90 days. Should he deny it, he must state his reasons in the Federal Register. In case of denial or non-response after 90 days, the petitioner may, within the next 60 days, sue in district court to compel the Administrator to initiate the rulemaking proceeding requested in the petition. When the petition seeks issuance of a regulatory rule or order, as opposed to amendment or repeal, the Act authorizes a de novo proceeding, where costs and attorneys' and witness' fees are reimbursed in appropriate cases.²⁰ If the petitioner establishes to the court's satisfaction the existence of a risk satisfying one of the standards for regulatory rule issuance, the court must order the Administrator to initiate rulemaking. Judicial review of denial of petitions to repeal rules is relegated to the general provisions of the APA, for in these cases the Administrator will already have considered the need for regulation on the merits.²¹

The Use of "Quick" Microbial Tests

Adequate and fair administration of the TSCA will depend upon use of quick and inexpensive tests to evaluate the risks of chemicals. This is most evident with respect to new chemicals where the Administrator normally has but 90 days to decide whether to give the product a green light, to require testing, or to commence regulation before commercial production may begin.

The most difficult problems posed by contemporary chemicals are serious, irreversible chronic effects, such as cancer, birth defects and genetic mutations. The TSCA reflects the importance of these chronic health injuries, mentioning them specifically in at least four places.²²

While reliable and inexpensive toxicological techniques have long been available for evaluating the acute and subacute effects of chemicals, it has proved far more difficult, expensive, and time-consuming to identify agents that cause cancer (carcinogens) and genetic mutations (mutagens). Such effects do not appear promptly, so that even animal laboratory testing can prove slow and expensive. Standard laboratory animal feeding tests for carcinogenicity, for example, routinely last two years and cost up to $200,000 per chemical.²³

In recent years, a number of microbial tests for mutagenicity have been developed which provide indications of whether the tested chemical is mutagenic or carcinogenic to humans. Perhaps the best known of the new microbial tests is the Ames assay, which is composed of yeast cells and an "activator" from human liver microsomal cells designed to approximate human metabolic conditions.²⁴ In addition, a number of more complex mutagen testing systems have been developed involving laboratory animals, insects and even plants. In evaluating chemicals for mutagenic activity, the various tests are arranged in a three-tiered battery.²⁵ Typically, a test chemical will first be subjected to the Ames assay, which takes two to four weeks and costs $500-1200. If positive there, it will be subjected to a series of more costly but more reliable tests.²⁶

Given the significant time and cost savings from microbial tests, it is important to explore the extent to which their results can meet the requirements for regulatory action under the TSCA. To answer this question, it is necessary to assess the current status of scientific opinion concerning extrapolation from microbial mutagenicity results to human mutagenicity and human carcinogenicity, and to discern the congressional intent respecting regulation under the Act on the basis of unquantified risks.

Recent scientific literature on toxicology reveals that positive Ames assay activity is thought to give some indication that a substance may be a human mutagen. The scientific literature does not describe Ames activity as indicating a "risk" that the substance will cause mutations in humans, but describes it as showing the substance to have the "potential" to do so.²⁷ Higher levels of confidence are expressed in consistent results from the multiple-tiered system mentioned above. If a substance shows positive on both tier 1 (Ames assay "screening") and on one or more "tier 2" tests, scientists are likely to consider it a candidate for regulatory action.²⁸

The reliability of the Ames assay as an indicator of human carcinogenicity is also under intense debate in scientific circles. Proponents point to the close correlation between known carcinogens and assay activity: over 90 percent of known human carcinogens tested are positive in the assay. Moreover, a number of new chemicals positive in Ames have turned out on further study to be carcinogens.²⁹ Opponents,on the other hand, generally invoke the voluminous and inconclusive scientific literature dealing with the question whether mutations are involved in the cause of [6 ELR 10251] cancer.³⁰ Studies are currently in progress to refine the correlation by supplying a data base from additional testing.³¹

Meeting TSCA Standards

The scientific uncertainty surrounding extrapolation from microbial mutagenesis tests to human mutagenicity and carcinogenicity raises the question whether and to what extent Ames assay alone satisfies the regulatory standards of the TSCA. As noted earlier, the Act's standards mandating action to test, regulate or ban chemicals are precautionary, focusing on the "risk" of harm to health or the environment associated with commerce in the chemical.

The degree of risk required to justify action varies according to the kind of regulatory action being taken. The Act consistently distinguishes between the testing standards, which require only that there "may" be an unreasonable risk, and the standards for substantive regulation, which speak of chemicals that "present" and new chemicals that "will present" a risk.³² While the Ames test may not provide the kind of evidence required for substantive regulation, it appears, given the double attenuation expressed by the former standards, that Ames assay results will support a finding by the Administrator that a substance "may present an unreasonable risk of injury to health" for purposes of requiring testing of any chemical (§ 4) and extending the premarket notification ban on new chemical marketing pending such testing (§ 5(e)). The minimal nature of "may present" is also indicated by the alternate standard that triggers testing. This is not predicated on a degree of risk but only on the absence of data and experience sufficient to permit a reasonable determination or prediction of a chemical's health effects. If positive Ames assay results do not qualify as quantifiable scientific data, they nonetheless serve as a red flag indicating that more definitive data are needed before marketing can be allowed.

Further, and most significantly, the term "risk" appears intended in its lay rather than scientific sense in the TSCA. As noted earlier, technical usage restricts "risk" to phenomena sufficiently well understood to permit quantified prediction (through development of dose-response curves). Short of that, scientists speak of "uncertainty," or say that a substance has a "potential" effect. The Act, by contrast, adopts the value-based policy³³ that, at least with respect to new chemicals, diffusion in the environment and human exposure should not be allowed until effects are known with some confidence. That this is the congressional intent is again underscored by the alternative "wide exposure" standard for extending the premarket notification period for new chemicals pending testing. The conference committee report observes, in discussing court use of these tests, that failure to apply them

would frustrate the purposes of this section [§ 5] that suspect chemicals be adequately tested to determine their health and environmental effects before commercial manufacture or processing begins…. The objective of section 5 [is] to totally prevent environmental or human exposure to suspect new [chemicals] until adequate testing can be performed and the data evaluated.³⁴

Further support for relying on microbial screening test results to trigger testing obligations comes from recent chemical industry practice. For some time, chemical companies have made substantial use of the Ames assay and similar bacterial screening tests, presumably to screen chemicals in the process of development for mutagenic and carcinogenic activity.³⁵ While not conclusive, such behavior implies some level of confidence in the empirical predictive power of the tests.

Finally, at least with respect to synthetic chemicals, the evolutionaryperspective suggests a per se need for caution. Any chemical molecule not found in nature may be said to have the potential to harm biological organisms from bacteria to man.³⁶ This is because living organisms' internal defense and waste removal systems are not likely to be prepared to cope with substances of a kind that they and their evolutionary precursors never [6 ELR 10252] had to contend with in the natural universe. Some 9000 synthetics are now in large-scale commercial use, their domestic production totalling about 120 billion pounds annually in 1968. Of the 2 million known chemical compounds, only about 3000 have been tested for cancerous propensities and 1000 of these have shown some sign of being carcinogenic.³⁷ In this regard, it should be noted that the TSCA is concerned with injury to the environment as well as human health, and § 3(5) defines "environment" to encompass "all living things" in the inanimate environment. Whatever may be the merits of extrapolating from Ames activity to humans, Ames assay results seem adequate to demonstrate potential risks to a wide range of simpler organisms.

If the Ames assay satisfies the TSCA §§ 4 and 5 testing requirements, it should prove reasonably easy for the EPA Administrator to handle evaluation of new chemicals during the 90-day premarket notification period. Since the notice of intended marketing must contain the technical name and molecular structure of each new chemical, it may be possible to prepare a quantity of the chemical for screening; in some cases, proponents may supply samples. Alternatively, in many cases the manufacturer will submit Ames assay results with the premarket notification. As noted above, many companies are now routinely doing screening tests and § 5(d)(1)(B) requires the marketing notice to include any test data concerning effects of the new chemical in the possession of the person giving notice. Of course, if the person submitting premarket notification submits data going beyond microbial screen results — such as mutagenicity tests on tiers above the level of the Ames assay and chronic rodent feeding tests for carcinogenicity — these would carry more weight than a positive Ames test result. The current EPA carcinogenesis policy reflects this ordering of the weight of evidence. For assessing carcinogenesis data, it states:

[T]he best evidence that an agent is a human carcinogen comes from epidemiological studies in conjunction with confirmatory animal tests. Substantial evidence is provided by animal tests that demonstrate the induction of malignant tumors in one or more species…. Suggestive evidence includes … indirect tests of tumorigenic activity, such as mutagenicity, in-vitro cell transformation … tests….³⁸

Conclusion

Should the Administrator rely solely on microbial screening test results to promulgate a § 4 rule requiring testing of a chemical or to maintain the premarket status quounder § 5(e) pending testing of a new chemical, the affected manufacturer or processor might choose to challenge such administrative action by petitioning a court of appeals for review or by resisting the marketing ban extension to force the Administrator to go to court under § 5. The manufacturer's chance of success in either course of action would be poor. With respect to the marketing ban extension order, the district court must apply the same standard as the Administrator. And, as indicated, the language and conference report comments make clear the need to act against chemicals because of, not despite, the lack of more reliable data. Too, the intrusiveness of the action in question is minor and its duration temporary, so the affected party cannot claim substantial harm. As regards testing rules, these may be more trouble because of the applicability of the substantial evidence test in the court of appeals, but again it is an absence of sufficient data that justifies testing. Moreover, some courts of appeals have recently evinced a growing recognition of the need for precautionary administrative action based on risk assessment rather than the usual factual record.³⁹ Just as they have learned to accept extrapolation from mice to men on questions of carcinogenicity, they may be prepared to accept projections from microbes to men as far as both cancer and mutations are concerned.

1. Public Law 94-469, 90 Stat. 2003 (eff. Jan. 1, 1977). Many of the Act's regulatory provisions will become effective six months to one year after the Act's effective date. For a comparison of the bills as originally passed by the House and Senate, see Comment, In Anticipation: Comparing the 1976 Toxic Substances Control Bills, 6 ELR 10138 (July 1976).

2. Risks are evaluated throughout the "life cycle" of chemicals, which the Act consistently defines as "manufacture, distribution in commerce, processing, use or disposal, … or any combination of such activities…."

3. § 4. Provision is made to avoid duplicate testing and to compensate persons who run tests for their use by others. The Administrator may charge fees up to $2,500 to defray the costs of evaluating tests, § 26(b). An interagency advisory committee is formed to advise on such potentially hazardous chemicals.

4. § 6 This section also requires PCB's to be phased out within three years.

5. § 7.

6. § 5(a). New chemicals are those not listed by the Administrator in an inventory of chemicals produced or processed in the United States that he is to compile under § 8(b). Notification must also be given for new uses of existing chemicals, but only after the Administrator establishes these uses through rulemaking.

7. § 5(e)(2)(B); Toxic Substances Control Act Conference Report, H.R. Rep. 94-1679 84th Cong., 2d Sess. 69 (1976) [hereinafter cited as Conference Report].

8. § 5(f). The marketing bar may be extended pending completion of § 6 regulation by the Administrator or, if there is objection, by court injunction.

9. § 5(c).

10. § 8(a).

11. § 10(c). The Administrator also has inspection and subpoena power, § 11.

12. 5 U.S.C. § 552(b)(4), ELR 41015: "trade secrets and commercial or financial information obtained from a person and privileged or confidential."

13. 5 U.S.C. § 553, ELR 41002.

14. E.g., § 6(c). Reimbursement is also authorized for attorneys' and witness' fees and other costs of participation in regulatory rulemaking by parties found to represent important issues but to lack resources, § 6(c)(4).

15. Conference Report, supra note 7, at 102.

16. § 19.

18. § 20. Violations of the Act by private parties are also subject to criminal and civil penalties, § 16, and injunctive restraints, § 17.

19. § 21.

20. § 21(b)(4)(B), (C).

21. Conference Report, supra note 7, at 98.

22. See, e.g., § 4(b), "carcinogenesis, mutagenesis, and teratogenesis;" § 5(e), "priority attention to those chemicals … suspected of causing or contributing to cancer, gene mutations or birth defects." See also §§ 5(f), 10(c).

23. Gehring, Rowe & McCollister, Toxicology: Cost/Time, in Dow Chemical Co., I Chemicals, Human Health and the Environment 38 (1975).

24. Health, Education and Welfare Committee to Coordinate Toxicology and Related Programs, Methods for Determining the Mutagenic Properties of Chemicals 28-29 (draft, 1976).

25. Interview with Dr. David Brusick, Litton Biometrics, Inc. (Oct. 11, 1976).

26. "Tier 2" tests take roughly four months and cost $4000-7000; "Tier 3" take 6-10 months and cost $10,000-20,000. Id. See also Gehring, Rowe & McCollister, supra note 23.

27. National Academy of Sciences, Principles for Evaluating Chemicals in the Environment 171 (1975). See also Health, Education and Welfare Committee, supra note 24, at 33.

28. Id. at 34.

29. See, e.g., McCann, Choi, Yamasaki & Ames, 72 Proc. National Academy of Sciences U.S.A. 5135 (1975).

30. National Academy of Sciences, supra note 27, at 147.

31. A joint program is being carried on by the United States and Japan to build the data base. Interview with Dr. Virginia C. Dunkel, Coordinator, In Vitro Carcinogenesis Program, National Cancer Institute, Oct. 14, 1976.

32. Compare § 4(a), in which testing rules are triggered by a finding that commerce in a chemical "may present an unreasonable risk of injury" and that there are "insufficient data and experience" on which to "predict or determine" the chemical's effects and § 5(e), in which a new chemical is kept off the market pending completion of testing upon a finding that "available information is insufficient" and the chemical "may present an unreasonable risk" or "will be produced in substantial quantities" and there may be substantial harm or environmental exposure to it with § 6(a), which justifies general restrictions on commerce in a chemical on a finding that there is a "reasonable basis to conclude that such commerce presents or will present an unreasonable risk" and § 7, which authorizes seizure of a chemical found to present "an imminent and unreasonable risk of serious or widespread injury."

33. On the disinction between statistical quantification of risk as probability and the community's policy judgment as to what level of probability or uncertainty is acceptable, see W. Lowrance, Of Acceptable Risk (1976); National Academy of Sciences, supra note 27, at 88. Cf. Reserve Mining Co. v. EPA, 514 F.2d 492, 5 ELR 20596, 20606 (8th Cir. 1975), where the court's expert medical witness distinguished between scientific and public health evaluations of the "risk" posed by asbestos particles in Duluth, Minnesota's drinking water:

I would say that the scientific evidence that I have seen is not complete in terms of allowing me to draw a conclusion one way or the other concerning the problem of a public health hazard in the water in Lake Superior.

Now, when I turn, however, to the medical side of things, Your Honor, I am faced with the fact that I am convinced that asbestos fibers can cause cancer…. I can come to no conclusion, sir, other than that the fibers should not be present in the drinking water of the people of [Duluth and vicinity].

34. Conference Report, supra note 7, at 69.

35. Interview with Dr. David Brusick, supra note 25. See also Kolata, Chemical Carcinogens: Industry Adopts Controversial "Quick Tests," 192 Science 1215 (1976).

36. See B. Commoner, Foreward in Consumer Health and Product Hazards vii-viii (1974).

37. Dr. Umberto Saffiotti, Assoc. Director for Carcinogenesis of the National Cancer Institute, quoted in Wade, Control of Toxic Substances: An Idea Whose Time Has Nearly Come, 191 Science 541 (1976).

38. EPA, Interim Guidelines for Carcinogen Risk Assessment, 41 Fed. Reg. 21404 (May 25, 1976).

39. See Reserve Mining Co. v. EPA, 514 F.2d 492, 5 ELR 20596 (8th Cir. 1975); Ethyl Corp. v. EPA, __ F.2d __, 6 ELR 20268 (D.C. Cir. 1976), discussed in Comment, Precautionary Controls: D.C. Circuit Upholds EPA's Phase-Down of Gasoline Additives in Interest of Public Health, 6 ELR 10100 (May 1976). See also Comment, Projected Environmental Harm: Judicial Acceptance of a Concept of Uncertain Risk, 53 J. Urban L. 497 (1976).