Vincent F. Garry

Agricultural lung diseases.

Agriculture is considered one of the most hazardous occupations. Organic dusts and toxic gases constitute some of the most common and potentially disabling occupational and environmental hazards. The changing patterns of agriculture have paradoxically contributed to both improved working conditions and increased exposure to respiratory hazards. Animal confinement operations with increasing animal density, particularly swine confinement, have contributed significantly to increased intensity and duration of exposure to indoor air toxins. Ongoing research has implicated bacterial endotoxins, fungal spores, and the inherent toxicity of grain dusts as causes of upper and lower airway inflammation and as immunologic agents in both grain and animal production. Animal confinement gases, particularly ammonia and hydrogen sulfide, have been implicated as additional sources of respiratory irritants. It has become evident that a significant percentage of agricultural workers have clinical symptoms associated with long-term exposure to organic dusts and animal confinement gases. Respiratory diseases and syndromes, including hypersensitivity pneumonitis, organic dust toxic syndrome, chronic bronchitis, mucous membrane inflammation syndrome, and asthmalike syndrome, result from ongoing acute and chronic exposures. In this review we focus upon the emerging respiratory health issues in a changing agricultural economic and technologic environment. Environmental and occupational hazards and exposures will be emphasized rather than clinical diagnosis and treatment. Methods of prevention, from both engineering controls and personal respiratory perspectives, are also addressed.

Reproductive outcomes in the women of the Red River Valley of the north. I. The spouses of pesticide applicators: pregnancy loss, age at menarche, and exposures to pesticides.

In the current study, there was a modest but significant increase in risk (1.6- to 2-fold) for miscarriages and/or fetal loss occurring throughout the year in the spouses of applicators who use fungicides. There is a surprisingly significant deficit in the number of male children born to the spouses of fungicide applicators. First-trimester miscarriages occur most frequently in the spring, during the time when herbicides are applied. Use of sulfonylurea (odds ratio OR = 2.1), imidizolinone (OR = 2.6) containing herbicides, and the herbicide combination Cheyenne (OR = 2.9) by male applicators was statistically associated with increased miscarriage risk in the spring. Limited survey data from women who are the spouses of applicators did not show major alterations of long-term endocrinologic status (menarche, menopause, endometriosis). With regard to personal pesticide exposures, only women who engaged in pesticide application where there is direct exposure to these products are at demonstrable risk (OR = 1.8) for miscarriage. It was hypothesized that the overall reproductive toxicity observed in this population is, for the greater part, a male-mediated event. Clarification of exposure events leading to reproductive toxicity through direct measurements of exposure in both men and women is needed to resolve this issue.

Effect of hypoxia on carbon tetrachloride hepatotoxicity

The effect of hypoxia on carbon tetrachloride-induced hepatotoxicity was studied. Male rats were exposed to carbon tetrachloride for 2 hr in the presence of differing oxygen concentrations. Serum glutamate-pyruvate transaminase (SGPT) activities were measured 24 hr after the end of the exposure. Exposure of rats to 5000 ppm carbon tetrachloride in the presence of 100, 21, 12, or 6% oxygen resulted in SGPT activities of 489, 420, 3768, and 1788 I.U./l respectively. Exposure of rats to air and 0, 1250, 2500, 5000, or 7500 ppm carbon tetrachloride gave SGPT activities of 35, 32, 69, 420, and 2188 I.U./l respectively; when 12% oxygen was used, the corresponding SGPT activities were 32, 665, 691, 3768, and 4200 I.U./l respectively. Exposure of rats to hypoxia produced histopathologically detectable condensation of hepatic cytoplasmic material, and exposure to 5000 ppm carbon tetrachloride in the presence of air produced mild centrilobular necrosis, which was much more severe when rats were exposed to 5000 pm carbon tetrachloride in the presence of 12% oxygen. Hepatic microsomal conjugated diene concentrations were increased by hypoxia and by exposure to carbon tetrachloride, but no synergistic interaction was observed. Hepatic microsomal cytochrome P-450 concentrations were decreased after exposure to carbon tetrachloride, but were the same after exposure to carbon tetrachloride and 12 or 21% oxygen. Hepatic carbon tetrachloride concentrations were the same in rats exposed to carbon tetrachloride in the presence of 12 or 21% oxygen; hepatic chloroform concentrations were higher in rats exposed to carbon tetrachloride in the presence of air than in the presence of 12% oxygen. The covalent binding of [14C]carbon tetrachloride metabolites to hepatic microsomal lipids and proteins was increased markedly by hypoxia as compared with normoxia. The covalent binding of metabolites of carbon tetrachloride to cellular macromolecules may play a role in the potentiation of carbon tetrachloride toxicity by hypoxia.

Male reproductive hormones and thyroid function in pesticide applicators in the Red River Valley of Minnesota.

In the present effort, 144 pesticide applicators and 49 urban control subjects who reported no chronic disease were studied. Applicators provided records of the seasons pesticides used by product, volumes, dates, and methods of application. Blood specimens for examination of hormone levels were obtained in summer and fall. In the herbicide-only applicator group, significant increases in testosterone levels in fall compared to summer and also elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the fall were noted. With respect to fungicide use, in an earlier cross-sectional epidemiologic study, data demonstrated that historic fungicide use was associated with a significant alteration of the sex ratio of children borne to applicators. As before, among current study subjects it was noted that historic fungicide use was associated with increased numbers of girls being born. Lower mean total testosterone concentrations by quartile were also correlated with increased numbers of live-born female infants. A downward summer to fall seasonal shift in thyroid-stimulating hormone (TSH) concentrations occurred among applicators but not among controls. Farmers who had aerial application of fungicides to their land in the current season showed a significant shift in TSH values (from 1.75 to 1.11 mU/L). Subclinical hypothyroidism was noted in 5/144 applicators (TSH values >4.5 mU/L), but not in urban control subjects. Based on current and past studies, it was concluded that, in addition to pesticide exposure, individual susceptibility and perhaps economic factors may play a supporting role in the reported results.

Interactive hepatotoxicity of chloroform and carbon tetrachloride.

Abstract The effect of giving chloroform (0.2 ml/kg), carbon tetrachloride (0.1 ml/kg), and both chloroform and carbon tetrachloride to male rats was studied. Serum glutamate-pyruvate transaminase activity and hepatic triglyceride concentrations were not altered by the administration of chloroform or carbon tetrachloride, but were increased when both were given together. Hepatic glutathione concentrations and conjugated diene formation were not changed after giving chloroform, carbon tetrachloride, or both chloroform and carbon tetrachloride. Ethane expiration was increased in rats given both chloroform and carbon tetrachloride as compared to rats given chloroform or carbon tetrachloride. Carbon tetrachloride administration, alone or with chloroform, lowered hepatic cytochrome P-450 concentrations, but no synergistic effect was seen when both chloroform and carbon tetrachloride were given. The administration of both chloroform and carbon tetrachloride increased hepatic calcium concentrations as compared to rats fiven corn oil, chloroform, or carbon tetrachloride. Modest histopathological changes were observed in rats given chloroform or carbon tetrachloride, and marked changes were seen in animals given both chloroform and carbon tetrachloride. Thus, by several criteria of hepatotoxicity, subthreshold doses of chloroform and carbon tetrachloride are hepatotoxic when given together, and by other criteria, the toxic effect of carbon tetrachloride was increased when given with chloroform. The mechanism of this interaction is not understood, but may be attributable to the combined effects of phosgene formation and the initiation of lipid peroxidation.

Survey of health and use characterization of pesticide appliers in Minnesota.

We surveyed 1,000 randomly selected state-licensed pesticide appliers to improve our understanding of pesticide use and its potential health effects. Participants were stratified by pesticide class (herbicides, insecticides, fungicides, fumigants) to determine potential differences in health characteristics among different pesticide groups. A subset of 60 applicators, divided by pesticide class used, were studied for exposure-related cholinesterase (ChE) depression. ChE depression in excess of 20% was most frequent in fumigant applicators who did enclosed-space application, in addition to other pesticide application procedures (p < .05). Survey data demonstrated that the prevalence of all common chronic diseases considered together was significantly increased (p = .015) in fumigant appliers, compared with all other pesticide use groups. The frequency of chronic lung disease was also significantly increased in the fumigant applier group (p = .027). Curiously, two cases of a rare hematopoietic neoplasm--hairy cell leukemia--were identified in our study group (annual incidence 0.67/100,000 in Minnesota). Whether there is an association between this unique tumor and agricultural work is uncertain, and further study is needed in this regard.

Multi-endpoint biological monitoring of phosphine workers

The pesticide phosphine (PH(3)) is a suspected carcinogen and a known clastogen which has been shown to produce chromosome damage in agricultural workers. To confirm and extend these results we evaluated 22 phosphine appliers and 26 controls matched for age and smoking status. Two independent methods were used to evaluate exposure: fluorescence in situ hybridization (FISH) with whole-chromosome paints of chromosomes 1, 2, and 4 labeled in a single color to quantify translocations in peripheral lymphocytes, and the glycophorin A (GPA) assay to quantify phenotypically mutant (NØ or NN) erythrocytes. No differences in the frequency of translocations were found in the phosphine appliers compared to the controls, and no effect of cigarette smoking was observed. However, a significant increase in the frequency of translocations with age (P<0.0001) was seen. No effect of phosphine exposure or cigarette smoking was observed in the GPA assay. These results are in contrast to previous findings from this same population which showed an increase in chromosome aberrations among phosphine appliers. The results are most easily interpreted as supporting the effectiveness of the personal protective equipment that is now worn by the workers but which was not employed prior to and during the earlier studies.

Differential Induction of Sister Chromatid Exchange by Chemical Carcinogens in Lymphocytes Cultured from Patients with Solid Tumors

Three carcinogens with different requirements for activation were used to generate sister chromatid exchange (SCE) in cultured lymphocytes from 22 untreated patients with solid tumors. These data were compared to SCEs produced by incubating lymphocytes, from 44 normal persons, with the same carcinogens. In vitro treatments with butadiene epoxide (0.125 micrograms/ml) show no significant differences in the SCEs generated. However, in vitro treatment with mitomycin-C (0.04 micrograms/ml) did induce significant differences (p less than 0.05) in the distribution of the SCE scores. Treatment of the cultured cells with benzo(a)pyrene (10 micrograms/ml), a carcinogen requiring extensive metabolic activation, significantly (p less than 0.001) altered the distribution of the SCEs generated in vitro. The SCE data suggest that metabolic activities play an important role in the processing of carcinogens in solid tumor patients.

Ethylene Oxide Induced Sister Chromatid Exchange in Human Lymphocytes Using a Membrane Dosimetry System

In an earlier study, we demonstrated that human exposure to ethylene oxide (EO) during sterilization procedures was associated with increased sister chromatid exchanges (SCE) in cultured peripheral blood. To study further toxic and mutagenic properties of EO in vitro, we devised a membrane dosimetry system which can be used to expose lymphocytes in peripheral blood to specified amounts of EO. The system consists of an exposure chamber, cell culture dishes to which are applied plastic membranes of varying diameters and an infrared analyzer used to monitor ambient EO concentrations in the system. Aliquots of EO-exposed media were subjected to gas chromatography for quantitation. Our preliminary analyses of the cultured cells indicate that the membrane dosimetry system we developed is capable of reproducibly delivering quantities of EO to target cells. Elevated SCEs were observed at as little as 10 micrograms/ml (in media) during a 20-min exposure period. A significant dose-response relationship between SCE and EO dose was recorded up to 35 micrograms/ml, the highest dose tested. Lymphocytes at 35 micrograms/ml showed a fourfold increase in SCE compared to control cultures. We conclude that the membrane dosimetry system provides a reproducible method to investigate EO mutagenesis in human cells in vitro and may prove applicable to a wide range of mutagenic gases.

Sister chromatid exchanges in adult epilepsy patients on valproate monotherapy

Sister chromatid exchanges (SCE) were studied in peripheral lymphocyte cultures of 13 adult male patients with epilepsy treated chronically with valproate (VPA) and in their matched controls. No statistically significant differences in SCE level were found between the patient and control groups, indicating a lack of mutagenic potential of VPA within the therapeutic dose range.