It is generally recognized that pesticides may pose a hazard to human health. Possible adverse health effects include cancer, birth defects, adverse effects on reproduction and development, damage to genetic material and other effects that may impair health. For this reason, an extensive battery of toxicity studies is required to determine the nature and extent of the hazard posed by a pest control product proposed for use in Canada.
The required studies are designed to assess the possible adverse health effects on a variety of species that may result from single, multiple or life-time exposure to a pest control product via the skin, mouth, lungs or eyes. A variety of species are used to indicate whether the same effects are observed in different species, or if they are limited to a certain species. Metabolic and toxicokinetic information are also key, because they provide valuable information on rates of absorption, distribution and excretion in mammalian systems, as well as a profile of metabolites that are likely to be present.
The following is a description of major studies that could be found in the health portion of a data package. In addition to being conducted on the pesticide itself, studies may also be conducted on metabolites.
Acute toxicity studies
Acute toxicity studies are designed to provide information about adverse health effects that may result within about two weeks of exposure to high doses of pesticides. A typical acute toxicity data package comprises studies that determine the bodily effects resulting from the most common routes of exposure (mouth, skin and lungs), as well as skin and eye irritation and skin sensitization studies. These studies provide the information necessary to make recommendations for safe handling practices, and help to indicate appropriate doses for longer-term studies. Acute hazards are indicated on the product label to prevent poisonings.
Short-term toxicity studies
Short-term toxicity studies determine the effects of repeated exposure to a pesticide over a short period of time, usually from three weeks to three months. These studies also examine effects resulting from the most common routes of exposure (mouth, skin and lungs). The results of these studies enable toxicologists to identify the tissues and organs that are susceptible to damage from exposure to a range of pesticide doses, to establish doses that are tolerated by the test animals, and to determine suitable doses for use in long-term toxicity studies.
Long-term toxicity and carcinogenicity studies
Long-term toxicity and carcinogenicity studies determine the effects of exposure to a test substance over most of the test animal's lifetime (e.g., 2 years for rats, 18 months to 2 years for mice). Extensive information on systemic toxicity and carcinogenicity is generated through the examination of organs and tissues, as well as through the biochemical and pathological analysis of blood and urine. It is critical that the doses selected for the conduct of these studies provide a range of responses, including a dose(s) that results in no observable adverse effects and a dose(s) that results in overt toxicity.
Reproductive and developmental toxicity studies
Reproductive and developmental toxicity studies are designed to generate information on possible effects on growth and reproduction, and are conducted over at least two generations. The dosing period includes pre-treatment of males through the period of sperm development and of females through at least one ovulatory cycle. The offspring are exposed to the pesticide through the maternal milk supply until weaning, when they are fed diets containing the pesticide.
Teratology studies are designed to determine whether a chemical may cause adverse effects on the developing fetus. The test substance is administered to pregnant animals during the most sensitive stages of development. These studies provide evidence regarding toxicity to the pregnant animal, as well as to the embryo and fetus.
Genetic toxicity studies
Genetic toxicity studies are conducted to determine whether the pesticide may interact with genetic material, resulting in mutations and other damage (e.g., chromosome breaks), or interference with normal genetic processes. This information is often used in conjunction with information from the carcinogenicity assessment to help determine possible mechanisms of action for observed effects.
Metabolism and toxicokinetics studies
Metabolism and toxicokinetics studies provide information about the relative amount of the product that is likely to be absorbed into the body, the relative distribution of the absorbed dose among the tissues, and the rates and routes of excretion (e.g., urine, feces, bile, expired air). Metabolites are identified, as is the relative proportion of each metabolite that may be expected through mammalian metabolic pathways.
Neurotoxicity studies are required for pesticides, such as organophosphorous insecticides, that are likely to affect nervous tissue. A variety of neurotoxicity studies may be required to determine a pesticide's mechanism of neurotoxic action.
Immunotoxicity is evaluated in the course of examining subchronic and chronic toxicity studies. Certain parameters, such as organ weights (e.g., thymus, spleen) and/or differential white blood cell counts, provide an indication of potential interference with normal immune function. If a concern is identified, further specific immunotoxicity studies may be required.
Endocrine disruptor potential
Endocrine disruptor potential (such as interference with the production of sex hormones) is evaluated in the course of examining the information from reproduction, teratology, and short- and long-term toxicity studies. If the results of these studies indicate the need for further information regarding interference with normal endocrine function, additional testing may be required.
Alternatives to animal tests
The scientific community is devoting a significant amount of effort to the development of alternatives to animal testing, particularly in the area of eye irritation. Efforts include the development of in vitro methods. In addition, computer programs are available that may predict potentially-hazardous materials through structure/activity relationships. At present, these alternatives are of limited use in regulatory programs where more reliable information from animal tests is still routinely required. However, they are quite useful in determining priorities for testing chemicals that have not been subjected to rigorous toxicity testing.
Health risk assessment
Risk assessment combines the results of the hazard assessment (i.e., the evaluation of scientific studies) with those of the exposure assessment. Scientists in the Pest Management Regulatory Agency (PMRA) determine the no observed adverse effect levels (NOAELs) from the information provided by the studies described above.
Cancer risk assessment
Assessment of cancer risks involves challenges that warrant special consideration. The PMRA's approach to cancer risk-assessment is based on the weight of the scientific evidence obtained through the evaluation of the entire data package.
Occupational/bystander risk assessment
In occupational/bystander risk assessments, the most appropriate NOAEL (based on such considerations as route and duration of exposure, species tested in toxicity studies, and the endpoint of toxicological concern) is divided by estimated exposure to determine the margin of safety. Typically, a margin of safety of 100 is considered acceptable to account for potential variability in response, both within the same species (i.e., adults versus children) and between species (i.e., rodents versus humans).
Food residue safety assessment
In evaluating the safety of food residues, the most appropriate NOAEL is divided by a safety factor, usually of 100. This number may be lower or higher, depending on a number of factors considered in the hazard assessment, such as the type of effect observed. The resulting figure provides the acceptable daily intake-the amount of the pesticide that toxicologists consider safe for humans to consume each day for an entire lifetime. A maximum residue limit is established for each food by first determining the amount of pesticide likely to remain in or on food at the point of sale. The maximum residue limit is accepted only if total consumption of residues from all foods (including consideration of different consumption patterns, such as those of children) will not exceed the acceptable daily intake for that particular pesticide.
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