At the federal level, four agencies are chiefly responsible for regulating human exposure to toxic materials: the FDA, EPA, OSHA, and the Consumer Product Safety Commission (CPSC). Together they administer over two-dozen statutes whose primary goal is the protection of health. The statutes administered by these four agencies utilize different regulatory approaches and require divergent safety benchmarks. This diversity has several explanations. The statutes were enacted in different eras. They originated with different political constituencies and remain under their influence. Perhaps most significant, statutory standards often reflect differences in the technical capacity to control different types of exposures, and they embody different Congressional judgments about the economic implications of limiting exposures.
Food and Drug Administration
The oldest of the major health regulation laws, the FFD&C Act, was originally enacted in 1906 and, as amended over time, now covers food for humans and animals, human and veterinary drugs, medical devices, and cosmetics.
The initial Food and Drug Act enacted in 1906 prohibited “adulterated” foods that contain “any poisonous or deleterious substance, which may render it injurious to health.” This provision, which remains in the statute to date [FFD&C Act § 402(a)], does not require premarket approval of foods and puts the burden of proof on FDA to demonstrate that a food meets the definition of “adulterated.”
Congress has since amended the act several times to strengthen the FDA’s ability to ensure the safety of foods (FFD&C, 1938). The most important of these amendments was the 1958 Food Additives Amendments that require the safety of food additives to be demonstrated prior to marketing (Food Additive Amendments, 1958). The manufacturer of a food additive must submit a petition demonstrating that the substance is “reasonably certain to be safe”; no inquiry into the benefits of an additive is undertaken or authorized (Cooper, 1978). Two categories of nonnaturally occurring food ingredients were exempted from this food additive requirement: (a) substances generally recognized as safe among experts qualified by scientific training and experience to evaluate safety; and (b) substances that either FDA or the US Department of Agriculture (USDA) had sanctioned for use in food prior to 1958 (so-called “prior sanction” substances).
Separate regulatory standards have been developed for several classes of indirect food constituents. For example, a food-contact substance requires approval as a food additive if, when used as intended, it “may reasonably be expected to become a component of food.” In 1997 omnibus legislation that addressed most of FDA’s regulatory programs, Congress created a new premarket notification system for food-contact materials that permits the agency to delay introduction if it questions a material’s safety, but does not require affirmative agency approval (FDA Modernization Act, 1997).
Preclinical studies in animals play an important role in the FDA’s evaluation of human drugs. The current law requires premarket approval, for both safety and efficacy, of all “new” drugs, a category that embraces virtually all prescription drug ingredients introduced since 1938 (Hutt et al., 2007). Premarket approval of therapeutic agents for commercial use primarily relies on randomized controlled trials in human subjects to establish safety and efficacy. However, animal and in vitro studies are the primary source of information about a substance’s biological effects before human trials are begun, and their results influence not only the decision whether to expose human subjects but also the design of clinical protocols. The FDA reviews the clinical evidence before authorizing human clinical trials through review of an Investigational New Drug (IND) application.
In 1976, Congress overhauled the FFD&C Act’s requirements for medical devices, providing the FDA major new authority to regulate their testing, marketing, and use. The elaborate new scheme contemplates three tiers of control, the most restrictive of which (class III) is premarket approval similar to that required for new drugs. To obtain FDA premarket approval of a class III device, the sponsor must demonstrate safety and efficacy. The bulk of the data supporting such applications will be derived from clinical studies but also will include toxicology studies of any constituents likely to be absorbed by the patient.
The statutory provisions governing cosmetics do not require premarket approval of any ingredient, or demand that manufacturers test their products for safety, though many manufacturers routinely do so. The basic safety standard for cosmetics is similar to that for food ingredients: no product may be marketed if it contains “a poisonous or deleterious substance, which may render it injurious to health” [FFD&C Act § 601(a)]. The case law establishes that this language, too, bars distribution of a product that poses any significant risk of more than transitory harm when used as intended, but it places on the FDA the burden of proving a violation (Hutt et al., 2007). The FDA has brought few cases under this standard, in part because acute toxic reactions to cosmetics are readily detected and immediately result in abandonment of the offending ingredient. The FDA also relies on the Cosmetic Ingredient Review (CIR), a private expert assessment body established in 1976 and operated by the Personal Care Products Council. The CIR appoints an expert panel that conducts safety assessments of cosmetics ingredients that are subject to public review and comment and then published as monographs.
Environmental Protection Agency
The EPA is responsible for administering most of the nation’s environmental laws, which include protection of both human health and the environment. A comprehensive review of the EPA’s numerous programs is not possible here; the following summary focuses on those EPA activities in which toxicology evidence plays a central role: the agency-wide Integrated Risk Information System (IRIS) program, pesticide regulation, regulation of industrial chemicals, regulation of drinking water supplies, hazardous waste control, and regulation of toxic pollutants of water and of air.
EPA’s IRIS provides an agency-wide scientific assessment program to evaluate the carcinogenic and noncarcinogenic human health risks of various chemicals. EPA prepares a Toxicological Review for a chemical, which goes through a series of internal and external reviews before being finalized, that is then used to derive a RfD and/or inhalation RfC for noncarcinogenic effects, and a weight of evidence determination as well as oral and inhalation unit risks for carcinogenic effects. IRIS values are used to support a variety of agency regulatory programs, including many of those described below. As of 2011, the agency has established IRIS values for over 550 chemical substances. EPA is in the process of reforming its IRIS process in response to criticisms of recent reviews, including a critical National Research Council study of EPA’s IRIS assessment of formaldehyde (NRC, 2011).
Pesticides are subject to two types of regulation: (i) registration under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA, 1972), which is required for a pesticide to be marketed in the United States; and (ii) tolerance (under the FFD&C Act), which sets the allowable level of pesticide residue in food for human consumption. Pesticide residues on raw agricultural commodities for years were initially regulated by the EPA under a 1954 amendment to the FFD&C Act, which allowed the agency to consider in setting tolerances both the potential adverse health effects of residues and the benefits of pesticide uses. If the concentration of a pesticide in a processed food exceeded the established tolerance, or the pesticide was a carcinogen, the Delaney clause prohibited its approval for that use (Les v Reilly, 1992). This framework was revised by Congress in 1996 by the Food Quality Protection Act (FQPA) to exempt pesticide residues from the operation of the Delaney clause but also restricted the consideration of pesticide benefits in setting tolerances.
The FQPA integrated the standard for registration and tolerance of a pesticide to require a pesticide to be shown to be safe, a standard defined as “reasonable assurance of no harm” (FQPA, 1996). The 1996 amendments also introduced some additional novel elements to the tolerance process. First, it required EPA to determine the safe level of a pesticide residue in a cumulative context, considering “all anticipated dietary exposures and all other exposures for which there is reliable information” [21 USC § 346a(b)(2)(A)(ii)]. This includes other nonoccupational sources of exposure, including food, drinking water, and residential exposures [21 USC § 346a(b)(2)(D)(vi)]. EPA must also base its safety determination on a consideration of exposures to other pesticides that share the same mechanism of toxicity [21 USC § 346a(b)(2)(C)(i)(III)].
Second, the 1996 FQPA required EPA to give special consideration to the health of infants and children, by ensuring “that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue.…” [21 USC § 346a(b)(2)(C)(ii)(I)]. To implement this requirement, the statute directs EPA to “use an additional 10-fold margin of safety in assessing the risks to infants and children to take into account potential for pre- and postnatal toxicity and the completeness of the toxicology and exposure databases.” EPA can deviate from the 10-fold margin of safety “only if, based on reliable data, the resulting margin would be safe for infants and children” [21 USC § 346a(b)(2)(C)(ii)(I)]. EPA’s failure to provide a legally sufficient rationale for not applying the presumptive 10-fold extra safety factor for children has been found to be arbitrary and capricious by reviewing courts (NRDC v EPA, 2011; Northwest Coalition for Alternatives to Pesticides v EPA, 2008).
Third, EPA must develop a program to test for endocrine disrupting effects of pesticides. There has been a flurry of research over the past couple of decades addressing the identification and mechanisms of toxicity from endocrine-disrupting chemicals (Marty et al., 2011). The FQPA required EPA to “develop a screening program, using appropriate validated test systems and other scientifically relevant information, to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other endocrine effect as the Administrator may designate” [21 USC § 346a(p)(1)]. Although EPA was required to establish this program by 1999, it did not meet this deadline.
EPA has been moving forward nevertheless and has created an Endocrine Disruptor Screening Program, which involves a two-tier screening and testing process: In Tier 1 testing, EPA seeks to identify chemicals that have the potential to interact with the endocrine system. Tier 1 consists of 11 different assays, which are being applied to 67 pesticide ingredients on EPA’s initial list of chemicals to be tested, which was released in 2009. This initial round of testing was scheduled to be completed in February 2012. EPA proposed in 2010 a second list of 134 additional chemicals to be tested in Tier 1. In Tier 2, EPA will determine the endocrine-related effects caused by each chemical that indicated endocrine disruption activity in Tier 1, and obtain information about effects at various doses in order to enable risk assessment. The agency is in the process of developing and validating Tier 2 tests. One issue is whether in Tier 2 EPA should use traditional animal assays or in vitro and computational assays that are part of EPA’s ToxCast program.
After the FQPA of 1996, the pesticide registration process now includes a broader review of the human health impacts of the pesticide from commercial use of the pesticides on applicators and other individuals, as well as effects on the environment. The manufacturer of a pesticide must produce a variety of data from tests done according to EPA guidelines. EPA’s test guidelines, most recently revised in 2007, now encompass guidelines for 340 types of tests recommended for pesticides (40 CFR 158 and 161). These tests evaluate whether a pesticide has the potential to cause adverse effects on humans, wildlife, fish, and plants, as well as possible contamination of surface water or ground water from leaching, runoff, and spray drift. The potential human risks that are evaluated include both acute and chronic toxicity. The EPA then conditions the use of the pesticide on various protections to ensure that the pesticide is used safely, which are summarized on the pesticide label.
The EPA has been engaged in a comprehensive review of previously registered pesticides and “reregistration” of those that meet contemporary standards for marketing for approximately the past three decades. Under this program, many older pesticides have been subjected to comprehensive toxicology testing, including carcinogenicity testing, for the first time, and the results have required modification of the terms of approved use and, in some instances, cancellation for several agents. The FQPA required EPA to review the registration (“reregistration”) and tolerance of older pesticides. In addition, EPA initiated a new program in 2006 called “registration review” in which it intends to re-evaluate all pesticides every 15 years. Finally, EPA may initiate a “Pesticide Special Review” process whenever it discovers that the use of a registered pesticide may result in unreasonable adverse effects on people or the environment.
The TSCA was promulgated in 1976 (TSCA, 1976) to regulate all chemical substances manufactured or processed in or imported into the United States, except for substances already regulated under other laws. A chemical substance is defined broadly as “any organic or inorganic substance of a particular molecular identity.”
TSCA gives the EPA three main powers. First, the agency is empowered to restrict or even ban the manufacturing, processing, distribution, use, or disposal of a chemical substance when there is a reasonable basis to conclude any such activity poses an “unreasonable risk of injury to health or environment.” In determining whether a chemical substance presents an unreasonable risk, the agency is instructed to balance the costs of restricting the substance against the health benefits of the proposed regulation [TSCA § 6]. This trade-off approach to regulation has proved a major challenge to the EPA. The agency has exercised its regulatory authority under section 6 against only a handful of substances, and it’s most significant regulations, such as its attempted ban on asbestos products, have been struck down by the courts for failing to do an adequate cost-benefit analysis (Corrosion Proof Fittings v EPA, 1991).
Second, if the EPA suspects that a chemical may pose an unreasonable risk but lacks sufficient data to take action, TSCA empowers the agency to require testing to develop the necessary data. Similarly, it may order testing if the chemical will be produced in substantial quantities that may result in significant human exposure whose effects cannot be predicted on the basis of existing data. In either case, the EPA must consider the “relative costs of the various test protocols and methodologies” and the “reasonably foreseeable availability of the facilities and personnel” needed to perform the tests [TSCA § 4].
Finally, to enable the EPA to evaluate chemicals before humans are exposed, TSCA requires the manufacturer of a new chemical substance to notify the agency 90 days prior to production or distribution [TSCA § 5(a)(1)]. The manufacturer’s or distributor’s notice (called a pre-manufacturing notice or PMN) must include any health effects data it possesses. However, the EPA is not empowered to require that manufacturers routinely conduct testing of all new chemicals to permit an evaluation of their risks; Congress declined to confer the kind of premarket approval authority that the FDA exercises for drugs and food additives and the EPA exercises for pesticides.
In contrast, the European Union (EU) is implementing a much more aggressive regulatory program for chemical substances, known as the Registration, Evaluation, Authorization, and Restriction of Chemical substances (REACH) program. REACH puts the responsibility for ensuring the safety of chemicals on the companies that produce, import, and use chemicals. The program applies to both new and existing chemicals, and is phased-in over an 11-year period based primarily on the production volume of individual chemicals. REACH employs a tiered-testing approach, with the amount of initial testing determined by production volume. A technical dossier is required for all registered chemicals; however, only chemicals with a production volume of 10 or more tons per year require a chemical safety assessment documented in a chemical safety report. REACH allows the use of alternative testing strategies to evaluate specific endpoints in lieu of experimental testing; however, whole animal testing requirements exist for each level based on production volume.
In light of the limitations of TSCA and the more proactive approach of the EU REACH program, there are active proposals in Congress to modify and update TSCA. Although the details of TSCA reform remain undecided at the time of this writing, there is broad consensus that some type of reform is needed.
The two primary statutes regulating hazardous wastes in the United States are the Resource Conservation and Recovery Act (RCRA, 1976) and the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA, 1980). With some exceptions, the primary purpose of CERCLA is the cleanup of contamination from pre-existing hazardous waste sites, whereas RCRA regulates the generation, transport, and disposal of new hazardous wastes. Both RCRA and CERCLA have their own extensive lists of substances and waste streams of toxic materials that are defined as hazardous wastes. In addition, under RCRA, wastes that meet any of four “characteristics” are also treated as hazardous wastes. The four characteristics are ignitability, corrosivity, reactivity, and toxicity, and EPA has identified standardized protocols for determining whether a particular waste stream meets one or more of these characteristics. Under RCRA, EPA has developed standards for generators, transporters, and those who treat, store, or dispose hazardous wastes that are required to “protect human health and the environment.” The EPA’s regulations applicable to generators and transporters establish a manifest system that is designed to create a paper trail for every shipment of waste, from generator to final destination, to ensure proper handling and accountability. The agency has the broadest authority over persons who own or operate hazardous waste treatment, storage, or disposal facilities. Pursuant to the RCRA, it has issued regulations prescribing methods for treating, storing, and disposing of wastes; governing the location, design, and construction of facilities; mandating contingency plans to minimize negative impacts from such facilities; setting qualifications for ownership, training, and financial responsibility; and requiring permits for all such facilities (RCRA, 1976).
CERCLA, often referred to as Superfund, authorizes the cleanup of hazardous waste sites and provides for liability of persons responsible for releases of hazardous waste at these sites. EPA can conduct cleanup of hazardous waste sites itself, and then seek recovery for the costs from potentially responsible parties (PRPs), or it can direct one or more PRPs to conduct cleanup, who may then seek contribution from other PRPs for their share of the cleanup. Under CERCLA, EPA has created the National Priorities List (NPL), which is a list of hazardous waste sites that are deemed the most hazardous sites and eligible for use of federal funds for long-term clean-up, and the National Contingency Plan (NCP), which provides the guidelines and procedures needed to respond to releases and threatened releases of hazardous substances, pollutants, or contaminants. For sites on the NPL, EPA conducts a Remedial Investigation and Feasibility Study to support the risk management process, which includes a site-specific human health and ecological risk assessment.
The EPA has had responsibility for regulating toxic water pollutants since 1972. As originally enacted, Section 307 of the Federal Water Pollution Control Act required the EPA to adopt standards for toxic water pollutants that provided an “ample margin of safety”—a difficult criterion to meet for most toxic pollutants and arguably impossible for any known to be carcinogenic. Given EPA’s difficulties in complying with this statutory directive, Congress amended the statute in 1977 to focus standards on economic cost and technologic feasibility. In 1987, Congress amended the statute again to toughen standards for toxic pollutants. Under the prior law, the EPA had developed health-based “water quality criteria” for 126 compounds it had identified as toxic. These criteria essentially described desirable maximum contamination levels, which, because the EPA’s discharge limits were technology-based, generally were substantially lower than the levels actually achieved. The 1987 amendments gave what had been advisory criteria real bite by requiring that states incorporate them in their own mandatory standards for water quality and impose additional effluent limits on operations discharging into below-standard waterways (Heineck, 1989).
The 1974 Safe Drinking Water Act (SDWA) was enacted to ensure that public water supply systems “meet minimum national standards for the protection of public health.” Under the SDWA, the EPA is required to regulate any contaminants “which may have an adverse effect on human health.” Over time and several Congressional amendments, this system has evolved into a two-tier system in which EPA adopts for each contaminant a maximum contaminant level goal (MCLG) that represents the optimal level to be achieved to ensure safety and the usually less stringent, feasibility-based maximum contaminant level (MCL). Only the MCL is legally enforceable. As part of the 1996 Safe Drinking Water Amendments, Congress directed EPA to use the “best available science” in setting MCLGs and MCLs.
The original 1970 version of the CAA provision for regulation of hazardous air pollutants (section 112) required the agency to set emission standards for individual toxic pollutants that protect public health with “an ample margin of safety.” The implication of this language—that standards were to provide absolute safety without regard to the costs of emissions control—generated intense debate from the beginning and contributed to the EPA’s glacial pace of implementation. The EPA finally attempted to escape the strict language of section 112 when it issued a standard for vinyl chloride in 1986 in which the agency claimed it could consider costs and declined to adopt a standard dictated solely by safety. A court ruled that the EPA had improperly considered costs, but it did make clear that in determining what emissions level was safe, even for a carcinogen, the EPA was not obligated to eliminate exposure but rather was to “decide what risks are acceptable in the world in which we live” (NRDC v EPA, 1987).
Amendments to the CAA in 1990 responded to the difficulties presented by the strict health-based approach of old section 112. The statute now provides a list of 188 hazardous air pollutants, which EPA may modify by adding or deleting items. The EPA must establish national emissions standards for sources that emit any of the listed pollutants with a two-tier system of regulation. The EPA must first issue standards that are technology-based, designed to require the “maximum achievable control technology” (MACT) [CAA § 112(d)(2)]. If the MACT controls are insufficient to protect human health with an “ample margin of safety,” the EPA must issue residual risk standards [CAA § 112(f)]. The 1990 Amendments essentially define “ample margin of safety” for carcinogens by requiring the EPA to establish added residual risk limits for any pollutant that poses a lifetime excess cancer risk of greater than one in one million. However, as subsequently clarified in a judicial decision, while EPA must promulgate residual risk standards if the MACT standards do not reduce risks to one in one million, the residual risk standards are not required to reduce the risks to one in one million, but rather to 100 in one million (NRDC v EPA, 2008).
Occupational Safety and Health Administration
The 1970 Occupational Safety and Health Act requires employers to provide employees with safe working conditions and empowers OSHA to prescribe mandatory occupational safety and health standards (OSHA, 1970). OSHA’s most controversial actions involved its attempts to set occupational exposure limits for hazardous chemicals.
The Act specifies that in regulating hazardous occupational exposures, OSHA shall adopt the standard “which most adequately assures, to the extent feasible, on the basis of the best available evidence, that no employee will suffer material impairment of health or physical capacity” [OSHA § 6 (b)(5)]. Judicial challenges to OSHA standards have clarified OSHA’s responsibilities. In a famous case, the US Supreme Court overturned OSHA’s benzene standard because the agency had not shown that prevailing worker exposure levels posed a “significant” health risk (Industrial Union Department, AFL-CIO, v American Petroleum Institute, 1980). This prerequisite proved a major obstacle when OSHA attempted to establish standards for 428 air contaminants in a single proceeding in 1989. Although it found that OSHA’s generic approach to regulation was permissible in theory, a court vacated the standards because OSHA failed to show that each individual contaminant posed a “significant risk” at current levels (American Federation of Labor v OSHA, 1992). However, the Supreme Court earlier upheld OSHA’s cotton dust standard, rejecting arguments that the agency was obligated to balance the costs of individual standards against the benefits of reducing hazardous workplace exposures (American Textile Manufacturers Institute v Donovan, 1982).
Consumer Product Safety Commission
Of the four agencies discussed here, the CPSC has played the least important role in federal efforts to control toxic chemicals to date. The commission was created in 1972 by the Consumer Product Safety Act (CPSA, 1972) with authority to regulate products that pose an unreasonable risk of injury or illness to consumers. The commission is empowered to promulgate safety standards “to prevent or reduce an unreasonable risk of injury” associated with a consumer product. If no feasible standard “would adequately protect the public from the unreasonable risk of injury” posed by a consumer product, the commission may ban the product [CPSA § 8]. In assessing the need for a standard or ban, the agency must balance the likelihood that a product will cause harm, and the severity of harm it will likely cause, against the effects of reducing the risk on the product’s utility, cost, and availability to consumers.
The CPSC also administers the older Federal Hazardous Substances Act (FHSA, 1976). The FHSA authorizes the CPSC to regulate, primarily through prescribed label warnings, products that are toxic, corrosive, combustible, or radioactive or that generate pressure. The FHSA is unusual among federal health laws because it contains detailed criteria for determining toxicity. It defines “highly toxic” in terms of a substance’s acute effects in specified tests in rodents; substances capable of producing chronic effects thus fall within the “toxic” category. The FHSA contains another unique provision [FHSA § 2(h)(2)] specifically addressing the probative weight of animal and human data on acute toxicity: “If the [commission] finds that available data on human experience with any substance indicates results different from those obtained on animals in the above-named dosages or concentrations, the human data shall take precedence.”
The CPSC has prescribed labeling for products containing numerous substances that are acutely toxic. It has also acted to ban from consumer products several substances that pose a cancer risk, including asbestos, vinyl chloride as a propellant, benzene, tris(hydroxymethyl)aminomethane, and formaldehyde (Merrill, 1981).
In 2008, Congress adopted the Consumer Product Safety Improvement Act (2008), which significantly strengthened the CPSC’s enforcement authority, especially for children’s products, in response to a number of high-profile recalls of children’s toys. The Act imposes bans on products containing lead or phthalates that exceed stringent levels, and requires third-party testing of certain children’s products.