Chapter 31 - Risk Assessment and Risk Management: The Regulatory Process

Chapter 62 - Risk Assessment and Risk Management: The Regulatory Process

Risk management strategy under the toxic substances control act and the federal insecticide, fungicide, and rodenticide act

Use of Bacteriocins in Food: Regulatory Considerations

The US Environmental Protection Agency (EPA) regulates pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA). Under FIFRA, the EPA is authorized to regulate pesticides to ensure that their use does not cause unreasonable adverse effects to humans and the environment. Under FFDCA, EPA has the responsibility to establish tolerances for pesticide residues on food crops. A tolerance is the maximum allowable residue of a pesticide on food. Such regulatory oversight is designed to minimize risks while allowing the public to benefit from pesticide use. Prior to lawful use in commerce, a pesticide must be registered by the EPA, unless specifically exempted by regulation. Registrants of pesticides are responsible for submitting specific data to the agency to support the conclusion that the pesticide will not significantly increase the risk of adverse effects to humans or to the environment. Once a pesticide is registered by the EPA, it may be sold and distributed in the United States and used as specified on the approved label.

8 - Pesticide Residue in Foods

In the US, the safety of specific chemical substances is evaluated primarily under three statutes. Substances used as food additives, drugs and cosmetics are regulated by the Food and Drug Administration (FDA) under the Federal Food, Drug and Cosmetic Act (FFDCA). Chemical substances proposed for use as pesticides are regulated by the US Environmental Protection Agency (USEPA) under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), which imposes a host of data requirements for any submitter seeking to register the substance as an active ingredient. Industrial chemicals are regulated under the Toxic Substances Control Act (TSCA; Public Law 94–469), which was enacted by Congress in 1976 in response to a perceived need to limit exposure to “environmental chemicals” such as polychlorinated biphenyls (PCBs). As stated in the Act, its primary purpose is “to assure that…innovation and commerce in…chemical substances and mixtures do not present an unreasonable risk of injury to health or the environment” (TSCA, section 2(b)). TSCA requirements are different for existing substances and substances not yet in production (“new” chemicals). One of the first tasks of the newly created Office of Toxic Substances (now the Office of Pollution Prevention and Toxics; OPPT) was to assemble and publish a list of chemical substances already in commerce. This was accomplished in July, 1979 as the TSCA Chemical Substance Inventory, which listed approximately 50,000 substances then in production or being imported into the US. Since that time the Inventory has grown to include over 70,000 substances by the addition of new chemicals.

The regulatory requirements for ocular toxicity of nondrug FDA products and the EPA are designed to identify the hazard of the material and ensure that labels have the proper use instructions and warnings. This is different from the Food, Drug, and Cosmetic Act (FDCA) process for drug development which is designed to determine the risk based on the exposure of the investigational drug. The regulatory guidance for cosmetics falls under the FDCA and is focused on ensuring that manufacturers produce safe products with proper use instructions and eye warnings. Other consumer products are regulated by the Consumer Product Safety Commission (CPSC) under the Federal Hazardous Substances Act (FHSA). The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) is responsible for registering pesticides and ensuring safe and proper use. Development of new industrial chemicals is regulated by the Toxic Substances Control Act (TSCA). The regulatory guidelines associated with these acts provide recommendations to use the Draize eye test for evaluation of ocular toxicity. However, each regulatory guidance for different substance categories has slightly different guidance for the Draize eye test methodology, the interpretation of the results, and conclusions based on the results. While the standard test to evaluate ocular toxicity has been the Draize eye test since the 1940s, significant efforts are currently under way to develop and validate alternative assays to identify ocular toxicity hazard, replace the Draize eye test, and modify the regulatory landscape.KeywordsOcular ToxicityConsumer Product Safety CommissionAlternative AssayPremarket ApprovalOcular HazardThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Since the dawn of civilization, humans have utilized microbial organisms of various sorts for food and agricultural production. More recently, microbes have been used for pesticidal, and environmental management purposes. With the advent of the development of recombinant DNA technology to genetically alter microbes, it became necessary for Federal regulators to assess the appropriate level, format, and application of their regulatory authorities. In 1986, the Office of Science and Technology Policy issued the Coordinated Framework for Regulation of Biotechnology. The Coordinated Framework constituted a comprehensive regulatory policy for biotechnology that, in essence, concluded that no new statutory authorities were necessary to effectuate a robust and efficient regulatory program for the products of biotechnology. The Framework articulated a division of regulatory responsibilities for the various agencies then involved with agricultural, food, and pesticidal products. Thus, in accordance with the Framework, USDA APHIS regulates microbes that are plant pests under the Plant Protection Act (PPA) and the National Environmental Policy Act (NEPA); the U.S. Environmental Protection Agency (U.S. EPA) regulates microorganisms and other genetically engineered constructs intended for pesticidal purposes and subject to the Federal Insecticide Fungicide and Rodenticide Act (FIFRA) and the Federal Food Drug and Cosmetic Act (FFDCA). The U.S. EPA also regulates certain genetically engineered microorganisms used as biofertilizers, bioremediation agents, and for the production of various industrial compounds including biofuels under the Toxic Substances Control Act (TSCA). The focus of this chapter is the regulatory process for approval of the use of genetically engineered microbes under the oversight of the U.S. EPA. We will also consider instances where organisms may be exempted from oversight and the outlook for the application of GE microbes in the future. This chapter does not seek to serve as a guidebook for navigating the details of the regulatory process, but rather as an overview of key considerations in risk assessment and risk management.

Along with proper hand hygiene, disinfection of contaminated surfaces and medical instruments has been a key method of preventing patient-to-environment-to-patient transmission of infectious agents via the hands of healthcare workers.1-3 However, there is growing concern regarding the increase in antibiotic-resistant pathogens for which environmental and device contamination may play a role in disease transmission, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Clostridium difficile, and multidrugresistant aerobic gram-negative bacilli (eg, Pseudomonas aeruginosa and Acinetobacter).1 Proper use of disinfectants plays an important role in reducing person-to-person transmission of these pathogens. For decades, the medical community in the United States has relied on the federal government’s disinfectant testing and registration program for assurance that registered disinfectants meet their label claims. However, recognized flaws in test methodologies could result in registration of ineffective disinfectants.4 Control measures should be instituted at the federal level to improve the test methodology and reduce the frequency of contaminated or ineffective disinfectants and the threat of serious healthcare-associated infections related to disinfectant use. We have previously reviewed the issues surrounding the selection and registration of high-level disinfectants and chemical sterilants.5 However, there are several unique aspects of testing and registration of low-level and intermediate-level disinfectants (eg, microbicidal testing methods) that warrant separate discussion. This article proposes a scheme for testing and registration of low-level and intermediate-level disinfectants that could be used by the U.S. Environmental Protection Agency (EPA). BACKGROUND Chemicals formulated as disinfectants in the United States are registered and regulated in interstate commerce by the Antimicrobial Division, Office of Pesticides Program, EPA. The authority for this activity was mandated by the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) in 1947. In June 1993, the U.S. Food and Drug Administration (FDA) and the EPA issued a “Memorandum of Understanding” that divided responsibility for review and surveillance of chemical disinfectants between the two agencies. Under the agreement, the FDA regulates disinfectants used on critical or semicritical medical devices and antiseptics and the EPA regulates disinfectants used on noncritical surfaces. In 1996, Congress passed the Food Quality Protection Act (FQPA). The Act amended FIFRA regarding several products regulated by both the EPA and the FDA. One provision of FQPA is that regulation of disinfectants used on critical and semicritical medical devices (the EPA continues to regulate non-medical disinfectants) was removed from the jurisdiction of the EPA and now rests solely with the FDA.1,6 Examples of disinfectants that are registered by the EPA with the intent of providing a public health benefit, therefore requiring efficacy data as a condition of their registration, include disinfectants used in hospitals and other healthcare settings on floors, walls, and medical equipment surfaces and household products claiming to have disinfectant activity. There are three types of disinfectant products that the EPA registers based on submitted efficacy data: limited, general or broad-spectrum, and hospital disinfectants. When a disinfectant is represented in its labeling for use in hospitals, medical clinics, dental offices, or any other medical-related facility, it must show

The Environmental Protection Agency (EPA) is committed to encouraging the development and use of biopesticides and considers them inherently reduced-risk pesticides. Biopesticides (microbial pesticides, biochemical pesticides, and plant-incorporated protectants) are required to be evaluated by EPA. The Agency must make findings of “no unreasonable adverse effects” to man and the environment to support its registration decision to permit sale and distribution under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), as well as a “reasonable certainty of no harm” under the Federal Food, Drug, and Cosmetic Act (FFDCA) to permit residues in food and/or feed. This chapter will review areas including how EPA views the benefits of biopesticides, related laws and legal requirements, biopesticide registration, and biopesticide data requirements. EPA’s commitment to low risk biological pesticides as alternatives to conventional chemical pesticides will also be emphasized.

The Environmental Protection Agency (EPA) is committed to encouraging the development and use of biopesticides and considers them inherently reduced-risk pesticides. Biopesticides (microbial pesticides, biochemical pesticides, and plant-incorporated protectants) are required to be evaluated by EPA. The Agency must make findings of “no unreasonable adverse effects” to man and the environment to support its registration decision to permit sale and distribution under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), as well as a “reasonable certainty of no harm” under the Federal Food, Drug, and Cosmetic Act (FFDCA) to permit residues in food and/or feed. This chapter will review areas including how EPA views the benefits of biopesticides, related laws and legal requirements, biopesticide registration, and biopesticide data requirements. EPA’s commitment to low risk biological pesticides as alternatives to conventional chemical pesticides will also be emphasized.

Under the Food Quality Protection Act (FQPA) of 1996 (Act), the United States Environmental Protection Agency (EPA) is mandated to conduct cumulative risk assessment on pesticides that act through a common mechanism of toxicity. Incumbent on the Agency is the development of sound scientific principles upon which to evaluate compounds for the presence of a common mechanism. Using the currently available draft guidance criteria, this paper employs five fungicides of the same general class, typified by captan, to evaluate both the criteria and the available scientific data. Captan and folpet are two chloroalkylthio fungicides currently registered with EPA under Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) for agricultural use. As such, these compounds are subject to the provisions of FQPA. Three additional fungicidal compounds—dichlofluanid, tolylfluanid, and captafol—are not registered for use in the United States; however, these five compounds have chemical structure and biological toxicity similarities and differences that permit their utility as test cases to determine what the EPA would conclude, with regard to common mechanism, if these draft guidelines were applied to these compounds. The results of the analyses are consistent and support the conclusion that captan and folpet share a common mode of toxicity for mouse duodenal tumors as defined in the Act. This common mode of toxicity is not shared by dichlofluanid, tolylfluanid, or captafol. The basis for concluding a common mechanism exists between captan and folpet. They include 1. Structural Similarity—The compounds are structural analogs having the identical biologically active moiety (i.e., the-SCCl3 side chain). 2. Mechanisms of Pesticidal Action—The compounds have the same mechanism of action. The overwhelming body of evidence suggests they are active because of their reactions with thiols. Both compounds, in reacting with thiols, produce similar degradates. Differences in rates of reaction are attributable to physical-chemical properties of the two compounds. 3. General Mechanisms of Mammalian Toxicity—The compounds induce mammalian toxicity through the same mechanism that is responsible for their pesticidal action, reactions with thiols. Another, albeit less likely, mechanism (for both compounds) is cross-Unking of proteins with DNA, although the extremely short half-lives of these compounds (seconds) argues against this possibility. 4. Sites of Action—Both compounds express their primary toxicity as local rather than systemic effects. 5. Common Toxic Endpoint—These two compounds induce gastrointestinal tumors (in mice only). 6. Mode of Action—Both compounds express their common toxic endpoint through a nongenotoxic, compensatory proliferation mechanism. 7. Specificity of Action—For both compounds, the majority of tumors appear in the duodenum. Furthermore, these tumors are induced only in mice. Repeated carcinogenicity testing suggests that rats are refractive to the effects of captan and folpet. The significantly faster hydrolytic rate for folpet at the lower pH values (e.g., increased 8-fold at pH 5) encountered in the stomach is believed to account for the tumors of the stomach observed with folpet and not captan. 8. Other Toxic Endpoints—For other toxic endpoints where comparative data are available, captan and folpet show similar patterns of toxicity (e.g., mutagenicity, skin sensitization, and acute toxicity).

In Response: A Government perspective.

The Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), enacted in 1947 and amended in 1972, 1978, and 1988, established federal regulation of pesticides in order to protect human and environmental health. FIFRA has been under the jurisdiction of the U.S. Environmental Protection Agency (EPA) since the EPA’s inception in 1970. Although FIFRA requires EPA to consider the benefits of a pesticide’s use, EPA must ensure that the pesticide is used without posing unreasonable adverse effects to human health or the environment. Furthermore, the Endangered Species Act (ESA), enacted in 1973, requires federal agencies to protect species vulnerable to extinction without consideration of costs. The amendments to FIFRA in 1972, 1978, 1988, and 1996 mandated the EPA review and reevaluate the eligibility of older pesticide products for reregistration under the updated FIFRA standard, while also complying with the new environmental laws of the 1970s. Today EPA’s goal is to review existing pesticide product registrations at least every 15 years under “Registration Review.” To meet their responsibilities under the ESA, EPA is initiating consultations with the U.S. Fish and Wildlife Service (USFWS) during the Registration Review process. The first pesticide active ingredients to advance to consultations under Registration Review are those in gas cartridge products. The U.S. Department of Agriculture’s Animal and Plant Health Inspection Service (APHIS) holds two gas cartridge product registrations. As a federal agency, APHIS also must comply with the ESA and consults with the USFWS on wildlife damage management activities, including tools such as pesticide products. This discussion presents APHIS’ unique ground view as a federal agency navigating the EPA’s ESA consultations during the Registration Review process, and describes the mitigation measures and their impacts on APHIS Wildlife Services’ activities.

There is a large body of evidence that relates the consumption of fruit and vegetables with reduced risk of various types of epithelial cancers, such as gastric cancer. The effect has been seen for all types of fruit and vegetables, including raw (salad) vegetables, cooked vegetables, fresh fruit, dried fruit, and citrus fruit. In general, the estimated relative risk for cancer usually decreases with an increasing number of servings per week for both fruits and vegetables. While there is fairly convincing evidence that higher intakes of fruit and vegetables are associated with lower risk of epithelial cancer, there was a recent report published in the March issue of Consumer Reports magazine entitled "How Safe is our Produce?" This report raised some concern that the pesticide residues in certain foods would be hazardous to human health, especially in certain vulnerable subgroups such as children. Consumers Union, the publisher, analyzed the US Department of Agriculture's available pesticide residue data on over 27 000 food samples covering the period 1994 to 1997, and their resulting technical report formed the basis for the article. The Consumer Union's article had computed a "toxicity index" (TI) for each food. The TI is assumed to integrate measures of the frequency of pesticide detection, the levels of residues present and the relative toxicity of the detected residues, yielding an index of the relative toxicity loading of each food. The article emphasizes that the TI does not measure risk , per se, the degree of risk associated with pesticide residues in foods also depends on the food intake and on other factors such as dose frequency, other exposures, age, illness, and the like. In any case, the authors of the Consumer Union article use the TI to rank fruits and vegetables and make their recommendations, indicating that produce with scores more than 100 are "of concern". The foods which had the lowest TI values (10 or less) were frozen/canned corn, milk, US orange juice, US broccoli, bananas, and canned peaches. The foods with highest TI values (100 or more) included fresh peaches, frozen and fresh winter squash grown in the United States (US), apples, grapes, spinach and pears, and US-grown green beans. Individual food samples often have multiple residues on them. In the US survey, up to 37 different pesticides were detected in apples, and more than 20 in peaches, pears and spinach. The most important contributors to the TI included relatively few pesticides. Methyl parathion accounted for a large part of the TI values for apples, pears, green beans and peas, as well as peaches. The average methyl parathion residue on peaches tested in 1994-1996 was 0.055 parts per million. The current EPA reference dose for methyl parathion is 0.02 mg/(kg?day). Therefore, a 20-kg child should not consume more than 0.4 mg per day of this insecticide. Eating just 1 medium-sized peach with an average methyl-parathion residue would give that 20-kg child a dose of this neurotoxic insecticide that is almost 14 times higher than the reference dose of the US Environmental Protection Agency. Methyl parathion on peaches is an extreme example, but it is far from the only case in which a young child can ingest more than a safe dose of a specific pesticide by eating a single serving of a specific food. For instance, the high TI values for winter squash from the United States are almost entirely due to residues of dieldrin, a toxic insecticide that was banned in that country some 25 years ago, but which persists in agricultural soils. Dieldrin was found in 37% of fresh winter squash and 74% of frozen winter squash in samples tested for it in 1997. The majority of the positive samples had residues high enough to give a 20-kg child more than the reference dose of dieldrin in a 100-gram serving of squash. Similarly, if the child were to eat 100 grams of fresh spinach, the odds are about 1 in 12 that he or she would exceed the reference dose for the organophosphate insecticides dimethoate and omethoate or methomyl, a carbamate insecticide. Of course, the reference doses have, in principle, safety factors built into them, and eating a reference dose does not automatically mean that a child will suffer any adverse effects. But a possible weak point in the control of pesticides is pointed out: the confidence of safety may not be guaranteed for children and other vulnerable subgroups. The fact that a few toxic pesticides account for most of toxicity loading has important policy implications. The hazards to humans associated with residues can be drastically reduced by focusing risk management efforts on a few pesticide uses. The Consumer Union's report was careful in pointing out that they do not recommend eating fewer fruits and vegetables, since the health benefits of these foods far outweigh the risks from the pesticides they contain. However, the report gives the following recommendations by which any possible hazards could be decreased even further: Wash or peel fresh fruits and vegetables before feeding them to children (NOTE: Do not reduce the children's consumption of fruits and vegetables!) Buy organically grown apples, peaches, grapes, pears, green beans, winter squash and spinach, if they are available where you live. Choose a variety of foods; do not overdo it with any one fresh fruit or vegetable. The Consumer Union's report is of course based on the situation in North-America. One can argue on the relevance of the toxicity index created. This index may not be really representative of toxicity to humans. But, these criticisms aside, the report carries, in any case, an important message; namely, the unnecessary use of toxic and persistent pesticides should be stopped, and consumers should be made aware of the levels of various pesticides detected in food products. The fact that fruits and vegetables are good for you should not overshadow the fact that even fruits and vegetables should be produced using good agricultural practices which avoid the use of the worst and most problematic pesticides, which leave residues on fresh products. The consumers have to have the right to eat their vegetables and fruits without being exposed to harmful levels of synthetic pesticides.