Evaluation of the carcinogenic potential of pesticides. 3. Aliette.

Aliette, a fungicide compound, was evaluated for carcinogenic potential by the Health Effects Division of the Office of Pesticide Programs using a consensus peer review process and EPA's guidelines for risk assessment. Aliette was categorized as a group C (possible human) carcinogen based upon evidence of an increased incidence of combined benign and malignant urinary bladder tumors in a single study involving male Charles River (CR) CD rats. The bladder tumors occurred only at the unusually high top dose level of aliette that was tested (40,000/30,000 ppm). The compound was not carcinogenic in female CR-CD rats in the same study, or in CD-1 mice of either sex in a second study. Monosodium phosphite, the main urinary metabolite of aliette, was also not carcinogenic in male or female CR-CD rats. Aliette was not demonstrated to be genotoxic. No structural analogues of aliette were identified. The mechanism of action for the production of bladder tumors was not identified; however, it did not appear to involve a genotoxic effect, a carcinogenic effect of metabolites, or the formation of renal stones. The data were not found to be sufficient to quantify human cancer risk from aliette.

Evaluation of the carcinogenic potential of pesticides. 2. Methidathion.

The carcinogen potential of methidathion, a dimethoxyorganic phosphorus pesticide and cholinesterase inhibitor, was evaluated by the Health Effects Division of the Office of Pesticide Programs using a consensus peer review process and the EPA's guidelines for risk assessment. Methidathion was categorized as a Group C (possible human) carcinogen based upon evidence of an increased incidence of benign and malignant hepatocellular tumors, alone and in combination, in a single study involving male Chr-CD-1 mice. The compound was not carcinogenic in female Chr-CD-1 mice in the same study or in Sprague-Dawley rats of either sex in a second study. Methidathion was not genotoxic in a variety of in vitro or in vivo tests designed to detect DNA damage, chromosome aberrations, gene mutations, and sister chromatid exchange. Although methidathion was identified as being structurally similar to two other organophosphate insecticides, prothidathion and lythidathion, no toxicological data were available on either of these agents for comparative purposes. The biological information on methidathion was reviewed by the agency's FIFRA Scientific Advisory Panel who agreed with the category C designation for methidathion. The data were not found to be sufficient to quantify human risk to methidathion.

Evaluation of the carcinogenic potential of pesticides. 1. Acifluorfen.

The Health Effects Division of the Office of Pesticide Programs evaluates the carcinogenic properties of pesticides by a consensus peer review process in which all available biological information on a compound is evaluated according to EPA's guidelines for cancer risk assessment. In many cases, pesticides are also evaluated by an external group of accomplished scientists who comprise the Agency's Scientific Advisory Panel. The herbicide acifluorfen was evaluated by these processes and was classified as a Category B2 (probable human) carcinogen based upon evidence of an increased incidence of malignant, or combined benign and malignant, tumors in multiple experiments involving two different strains of mice. The compound produced benign and malignant liver tumors in male and female B6C3F1 mice and in female CD1 mice. Stomach papillomas were also observed in male and female B6C3F1 mice. Acifluorfen was mutagenic in bacteria and yeast, but not in mammalian cell systems. In addition, acifluorfen is structurally related to eight other diphenyl ether pesticides, all of which evoke liver tumours in mice or rats. The data were found to be sufficient to quantify human risk to acifluorfen.

The toxicological testing of metabolites.

The 1978 Office of Pesticide Programs Guidelines gave guidance to the registrant as to the type and nature of the toxicological studies required to register a pesticide in the United States (Federal Register, Aug. 22, 1978, Part II). The most rigorous data requirements are for pesticides used on food or feed. Usually for major studies such as oncogenicity, chronic feeding and multigeneration reproduction, the test substance is the technical material. The highest dose in these tests is one which is either the maximum tolerated dose or one which induces some toxic effects. Presently the Agency is attempting to harmonize Pesticide Guidelines with those acceptable to the Organization for Economic Cooperation and Development (OECD). When significant pesticide metabolites are found in food residues and these differ from animal metabolites then toxicity testing is needed for these products. The type and duration of testing is determined on an individual basis.