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4 METHODS FOR TOXICITY TESTING
Pages 127-158

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From page 127...
... . Data, including those derived from toxicity testing, crop residue analyses, environmental fate testing, and ecotoxicology testing, are generated by the manufacturer of a pesticide to meet the mandatory requirements of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)
From page 128...
... CURRENT METHODS: GENERAL CONSIDERATIONS Toxicity studies are required to assess potential hazards to humans through the acute, subchronic, and chronic exposure of laboratory animals to pesticides. The more specific types of toxicity that are determined include carcinogenicity; developmental (including teratogenicity in offspring)
From page 129...
... are useful for delineating mechanism of action, but for any material and adverse effect, some dose level exists for man or animal below which this adverse effect will not appear. This biologically insignificant level can and should be set by use of a proper uncertainty factor and competent scientific judgment....
From page 130...
... . The selection of dose levels for subchronic studies should be based on the results of acute toxicity testing, on range-finding studies, and on pharmacokinetic (metabolism, including rate in various tissues)
From page 131...
... This dose level is referred to as the limit dose and corresponds to approximately 20,000 ppm in the diet of rats, 7,000 ppm in the diet of mice, and 40,000 ppm in the diet of dogs. The duration of exposure for toxicity testing of a pesticide depends on the expected duration of human exposure to the pesticide in practice.
From page 132...
... EPA's toxicity testing requirements for food and nonfood use pesticides have been published in 40 CFR Part 158. In general, for a food use chemical with maximum human exposure, the following toxicity tests are required: · acute oral toxicity · acute dermal toxicity · acute inhalation toxicity · primary eye irritation · primary dermal irritation · chronic feeding toxicity · dermal sensitization · acute neurotoxicity · 90-day toxicity · 21-day dermal toxicity · 90-day neurotoxicity study · reproduction study
From page 133...
... Acute toxicity data also provide information used to determine the need for child-resistant packaging, for protective clothing requirements for applicators, and for calculation of farm worker reentry intervals. A minimum number of animals, usually adults, are used in these studies and only the end points of concern are monitored, i.e., mortality, observable skin or eye effects, dermal sensitization, and observable neurotoxic behavioral changes.
From page 134...
... statement Improper test material application/preparation Omitted source, age, weight, or strain of test animal Missing individual/summary animal data Control problems Dosing level problems Lack of characterization of the test material Unacceptable protocol or other protocol problems Individual animal scores or data missing Scoring method or other scoring problem Reporting deficiencies or no quality assurance statement A NOEL was not established Lack of characterization of the test material or incorrectly reported Lack of clinical chemistry and/or lack of histopathology Reporting deficiencies Lack of characterization of the test material A NOEL was not established An investigational parameter missing
From page 135...
... Information on the pilot study and other problems associated with dose level selection An investigational parameter missing Information on the pilot study and other problems associated with dose level selection Lack of characterization of the test material Raw data analyses incomplete or missing A systemic NOEL was not established Inadequate percentage of body surface area exposed in each dose group Insufficient number of dose levels tested Lack of characterization of the test material A systemic NOEL was not established Incomplete/missing raw animal data analyses Insufficient number of dose levels tested Poorly controlled test environment Missing histopathology information Missing information in study reports MTD was not achieved Missing historical control data Lack of characterization of the test material Deficiencies in reporting the study data Histopathology information missing MTD was not achieved Lack of historical control data Information missing in study reports Lack of characterization of the test material Deficiencies in reporting of study data Missing historical controls Lack of characterization of the test material Information missing or requiring clarification of the laboratories' methods Information missing or requiring clarification of the laboratories' results A NOEL was not established Statistical problems Did not use conventional assessments for skeletal or visceral examinations Clarification of laboratory procedures or interpretation of the data Individual maternal or fetal data missing Missing historical controls Lack of characterization of the test material Excessive maternal toxicity
From page 136...
... Information missing from laboratory results Lack of characterization of the test material Information missing or requiring clarification of laboratory methods or results Missing historical controls A NOEL was not established due to effects at the lowest dose tested Low fertility and/or inadequate number of animals were used per dose level A NOEL was not established in We absence of reproductive effects Metabolism Inadequate or missing data on identification of (85-1) metabolites Improper methodology or dosing regimen Inadequate number of animals were used in the dose groups No individual animal data Improper reporting Inadequate or missing tissue residue analysis data Testing at only one dose level Only one sex of animal used Lack of an intravenous dose group No collection of SCOW Dermal Penetration Incomplete/missing data evaluation (85-2)
From page 137...
... , rats selected for these studies should be started on the test material shortly after weaning, "ideally before the rats are 6 and, in any case, not more than 8 weeks old." For dogs, dosing should begin when they are 4 to 6 months of age and "not later than 9 months of age." Most subchronic toxicity studies monitor clinical or behavioral (neurological) signs of toxicity, body weight, food consumption, eye effects, certain plasma or serum and urine parameters, organ weights, and gross and microscopic pathology.
From page 140...
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From page 141...
... 141 ~ o ~C ,~ <~ ~ o C isbe ~ ~ .~ ,, ~ E it, :~ o c _ ~ = ~ J c4 ~ ~ ,0 e E ~ 9 ° 0)
From page 144...
... lymph nodes, oviduct, brain, stomach, pancreas, skin, mammary gland, rectum, heart, spleen, spinal cord, testes, musculature, thyroid/parathyroid, pituitary, epididymis, salivary glands, ileum, adrenals, thymus, trachea, urinary bladder, accessory sex organs, and gallbladder. The data described above are not required for all subchronic studies.
From page 145...
... , motor activity, and histopathological examination of the nervous system. CHRONIC TOXICITY STUDIES General Description Information derived from chronic studies is used to assess potential hazards resulting from prolonged and repeated exposure to a pesticide over a large portion of the human life span.
From page 146...
... DEVELOPMENTAL TOXICITY STUDIES General Description Developmental toxicity studies are designed to assess the potential of developmental effects in offspring resulting from the mother's exposure to the test substance during pregnancy. These effects include death of the developing organism, structural abnormalities, altered growth, and functional deficiencies.
From page 147...
... Again, only historical control data from studies on the same species and strain of animal should be used for comparison purposes. EPA's Proposed Changes At least one developmental toxicity (formerly teratogenicity)
From page 148...
... A reproduction study (Guideline 83-4; EPA, 1984) could also be required to support nonfood uses if adverse effects on the reproductive system or developmental toxicity are observed in other studies.
From page 149...
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From page 150...
... The revised guidelines would require an initial battery of tests consisting of: · Salmonella typhimurium reverse mutation assay; · mammalian cells in culture forward gene mutation assay allowing detection of point mutations, large deletions, and chromosome rearrangements; and · in viva cytogenetics. Results derived from these assays could trigger the requirement for further mutagenicity testing.
From page 151...
... If a major metabolite forms in the plant but not in the test animal, separate toxicity testing on the plant metabolite could be necessary. The extent of testing required depends on the level of concern raised by the initial battery of toxicity tests (acute and subchronic studies, one teratology study, and a battery of mutagenicity tests)
From page 152...
... . EPA's Proposed Changes The changes in the requirements for neurotoxicity testing were described above under "Acute Toxicity" and "Subchronic Toxicity." SPECIAL TESTING EPA intends to develop better definitions of the conditions under which domestic animal safety (Guideline 85-2; EPA, 1984)
From page 153...
... , immune, and endocrine systems to cite a few examples. Because the battery of acute toxicity tests now required by EPA is generally performed in adult animals, very little information is available on acute toxicity in immature animals.
From page 154...
... In utero exposure did not affect the occurrence of liver tumors in male and female mice, but did result in a sex-dependent increase in the number of malignant thyroid tumors in mice and rats (NTP, 1992~. · Measurement of the serum thyroid hormones T3 and T4 and serum TSH should be routinely added to the EPA chronic/carcinogenicity study protocol or to the subchronic toxicity protocol for the rat so that adverse effects on thyroid function can be determined earlier.
From page 155...
... The committee believes that because the human immune system is one of the most robust of systems in terms of resistance to pesticides or other chemical toxicity, initial evaluation using current histopathologic examination of spleen, lymph nodes, thymus, and bone marrow should be sufficient unless abnormalities are noted. · A modified reproductive/developmental toxicity study in the rat is suggested for registration of all food-use pesticides.
From page 156...
... 1991a. Pesticide Assessment Guidelines, Subdivision F: Hazard Evaluation-Human and Domestic Animals, Carcinogenicity of Ethylene Thiourea [CAS No.
From page 157...
... 1991b. Pesticide Assessment Guidelines, Subdivision F: Hazard Evaluation Human and Domestic Animals Series 84.


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