Toxicology of Chlorophenoxy Herbicides and Their Contaminants

Abstract

The chlorophenoxy herbicides produce contact dermatitis in humans, a rather severe type of dermatitis known as chloracne has been observed in workmen involved in the manufacture of 2,4,5-T. This effect appears due primarily to the action of a contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin. Pharmacokinetic studies in human volunteers have indicated that the biological half-lives of 2,4-D and 2,4,5-T are on the order of one to three days. As indicated, the toxicology of the chlorophenoxy herbicides is complicated by the presence, or possible presence, of polychlorinated dibenzodioxins (PCDD) contaminants. There is a fairly wide variation in species sensitivity to TCDD, with guinea pigs being most susceptible (oral LD50 0.6 mg/kg) and hamsters the most resistant (1,157 mg/kg). The toxic effects of repeated doses in laboratory animals include: systemic lesions involving liver, blood and skin, reduced fertility, fetotoxicity and teratogenicity, immunodeficiency, liver enzyme induction and carcinogenicity. Immunodefici3ency is also a sensitive indicator of TCDD effects in laboratory animals, occurring with about 100 nanograms/kilogram. With regard to humans, the most consistent finding among persons exposed to TCDD is the dermatologic condition known as chloracne. Peripheral neuropathy has been reported in several epidemiologic studies that have been conducted among workers who have had opportunity for exposure to 2,4,5-T, trichlorophenol or related polychlorinated dioxins. In a study of nerve dconductance velocities of fifty-six workers with a mean age of thirty-six and 7-year mean duration of employment in the manufacturing of chlorophenoxy herbicides, it was shown that, in relation to the control group, exposed workers had slowed conduction in the sural and the median motor nerves. The degree of slowing was correlated with the duration of employment. During the 1970's, concern about the toxicity of 2,4,5-T and related compounds centered primarily on the apparent teratogenic action in experimental animals. It was subsequently determined that those studies, which indicated fetrotoxicity and teratogenic effects of 2,4,5-T, were conducted with a sample of the herbicide that contained a high level (about 30 ppm) of TCDD. This highlights the importance of always taking into consideration the presence of minor contaminants that may be present due to formation during manufacture or from degradative reactions occurring in the environment, when evaluating the toxicological effects of a chemical. Various studies of the teratogenicity and fetotoxicity of 2,4-D have yielded inconsistent results and generally this herbicide is less suspect of teratogenic action than the trichlorinated analog. The potent fetotoxic agent 2,3,7,8 TCDD is not a contaminant of 2,4-D, although some related, less toxic, dioxins may be present in low concentrations. Another important controversy involving chlorophenoxy herbicides is the exposure of veterans of the Vietnam war to Agent Orange. When all incidents of malformation in babies fathered by veterans were considered, the odds ratio was 0.97 with 95% confidence limits of 0.83 to 1.14. This provided no support to the hypothesis that Vietnam veterans are at increased risk, in general, for fathering deformed babies than other men. However, the estimated risk for fathering babies with specific malformation of spina bifida was higher for Vietnam veterans which had higher Agent Orange Opportunity Index Score.These veterans also had higher estimated risk for fathering babies with cleft lip and with the broadly categorized defect "other neoplasms". The herbicide 2,4,5-T is among the ten pesticides that Vos et al.(1983)concluded had "marked" effects on the immune system. TCDD contamination is likely to be responsible for most of this effect. The chlorophenoxy herbicides or their contaminants have been sduspected contributors to increased insidence of soft-tissue sarcomas or malignant lymphomas in groups of workers who have opportunity for occupational exposure. Further interest in this subject was stimulated by epidemiological studies which found that farming and forestry occupations, particularly, had increased incidence of certain types of soft tissue sarcomas or lymphomas. Farmers that have been exposed to herbicides more than 20 days per year, had a six-fold increased risk of non-Hodgkins lymphoma relative to non-farmers. Several of the epidemiological studies reporting possible increased tumors associated with occupational exposure to chlorophenoxy hrebicides have been criticized on the basis that each of these studies, individually, often involve a very small number of cases. However, over the past few years there have been numerous independent reports of such incidents, and taken together they suggest reason for concern.