Showing papers in "Journal of Toxicology and Environmental Health in 1992"
TL;DR: Active oxygen species such as H2O2 may have an important role in the initiation of carcinogenesis within the target cell population of rats with a single carcinogenic dose of CdCl2.
Abstract: Treatment of rats with a single carcinogenic dose of CdCI2 (i.e., 30 nmol/kg) caused severe hemorrhagic damage in the testis within the first 12 h after the metal. Subsequently, atrophy with calcification developed in the next 2–3 mo. Atrophied tissues regenerated during the 1 yr after exposure. Twelve hours after exposure to the Cd treatment, lipid peroxidation levels, Fe content, and cellular production of H2O2 were remarkably elevated in testicular Leydig cells, the target cell population for Cd carcin‐ogenesis. At the same time, glutathione peroxidase activity rose, glutathione reduc‐tase and catalase activities were reduced, and superoxide dismutase activity was unchanged. Xanthine oxidase activity in Leydig cells was also elevated at 6 and 9 h after the Cd treatment. Reduced glutathione in testes was decreased and oxidized glutathione was increased 12 h after exposure to the metal. These facts suggest that the carcinogenic doses of Cd induced oxidative stress while compromising cellular defense mech...
161 citations
TL;DR: In this article, the LD50 for [14C]picric acid was established as 290 and 200 mg/kg, respectively, for both male and female rats, and the plasma half-life was 13.4 h with a gut absorption coefficient (ka) of 0.069 h−1.
Abstract: Picric acid (2,4,6‐trinitrophenol) is widely used in industry, by the military, and as a research/clinical chemistry reagent. Characterization of the toxicity of this chemical has been limited. Thus the acute toxicity, distribution, and metabolism of picric acid were investigated using Fischer 344 rats. The LD50 for picric acid following oral dosing of male and female rats was established as 290 and 200 mg/kg, respectively. Blood gas analysis indicated severe acidosis during acute intoxication. Metabolism of picric acid was limited to reduction of nitro groups to amines. Metabolites isolated from urine included N‐acetylisopicramic acid (14.8%), picramic acid (18.5%), N‐acetylpicramic acid (4.7%), and unidentified components (2.4%). Approximately 60% of the parent picric acid was excreted unchanged. The plasma half‐life for picric acid was 13.4 h with a gut absorption coefficient (ka) of 0.069 h−1. Twenty‐four hours following oral administration of [14C]picric acid (100 mg/kg), the primary depots of radioa...
158 citations
TL;DR: Current information from worker interviews and historical records from the National Archives and elsewhere were used to evaluate the accuracy of prior exposure estimates and to develop better ones for the Pliofilm cohort, and one of the key findings was that, unlike prior analyses, the three facilities probably had significantly different airborne concentrations of benzene.
Abstract: The Pliofilm cohort is the most intensely studied group of workers chronically exposed to benzene. Information on this cohort has been the basis for regulations and/or guidelines for occupational and environmental exposure to benzene. Rinsky et al. (1986, 1987) and Crump and Allen (1984) developed different approaches for reconstructing the exposure history of each member of the group. The predicted levels of exposure, combined with the data on the incidence of disease, have been used to estimate benzene's carcinogenic potency. In this paper, recent information from worker interviews and historical records from the National Archives and elsewhere were used to evaluate the accuracy of prior exposure estimates and to develop better ones for the cohort. The following factors were accounted for: (1) uptake of benzene due to short‐term, high‐level exposure to vapors, (2) uptake due to background concentrations in the manufacturing building, (3) uptake due to contact with the skin, (4) morbidity and mortality d...
100 citations
TL;DR: A large segment of the general population of the United States experienced exposure to certain pesticides, including some considered biodegradable, during the years 1976-1980, and preliminary analyses showed an apparent relationship between residue concentration and two measures of urine concentration (osmolality and creatinine.
Abstract: Residues of toxic chemicals in human tissues and fluids can be important indicators of exposure. Urine collected from a subsample of the second National Health and Nutrition Examination Survey was analyzed for organochlorine, organophos‐phorus, and chlorophenoxy pesticides or their metabolites. Urine concentration was also measured. The most frequently occurring residue in urine was penta‐chlorophenol (PCP), found in quantifiable concentrations in 71.6% of the general population with an estimated geometric mean level of 6.3 ng/ml. Percent quantifiable levels of PCP were found to be highest among males. Quantifiable concentrations of 3,5,6‐trichloro‐2‐pyridinol (5.8%), 2,4,5‐trichlorophenol (3.4%), para‐nitrophenol (2.4%), dicamba (1.4%), malathion dicarboxylic acid (0.5%), malathion alpha‐monocarboxylic acid (1.1%), and 2,4‐D (0.3%) were found, but at much lower frequencies. No quantifiable levels of 2,4,5‐T or silvex were found. Preliminary analyses showed an apparent relationship between residue concent...
92 citations
TL;DR: TNT was mutagenic for Salmonella typhimurium without the need of a rat liver metabolic activation system (S9), and Tetryl behaved like TNT, except that it was approximately three times more potent.
Abstract: TNT was mutagenic for Salmonella typhimurium without the need of a rat liver metabolic activation system (S9). The mutagenic potency of TNT decreased in proportion to the number of nitro groups that were reduced to the amino form. The presence of a nitro group on the 4 position of the diamino congener is necessary for mutagenicity. Among the active congeners, mutagenicity was generally greater for TA100 than TA98, except that for the 4-amino congener the reverse was true. In cases when S9 was included in the assay, there was always a decrease in the number of mutants induced as compared with those without S9. Tetryl behaved like TNT, except that it was approximately three times more potent. RDX and HMX were not mutagenic under the conditions of the assay. When TNT was composed, the major metabolites identified in organic extracts of compost samples were the 2-amino and 4-amino congeners. An acetonitrile extract of compost was tested and found to be more mutagenic for TA98 than TA100, much like the authentic 4-amino congener, but the amount of this congener in the extract did not account for the degree of mutagenicity.
92 citations
TL;DR: To quantitate leaching from treated clothing, studies were performed in which swatches of fabric impregnated with 14C-labeled permethrin were applied to the backs of rabbits for 1 wk and migration was quantitated by measuring the fate of the 14C label.
Abstract: Permethrin is an agricultural insecticide of great interest to the military because of its repellency toward disease-bearing insects when impregnated into uniforms. However, migration of the substance from clothing to the skin surface is of toxicological importance. To quantitate leaching from treated clothing, studies were performed in which swatches of fabric impregnated with 14C-labeled permethrin were applied to the backs of rabbits for 1 wk. Permethrin migration was quantitated by measuring the fate of the 14C label. Conditions that could affect leaching and/or absorption were also evaluated, that is, varying environments, the presence of sweat, different fabric types, and the effects of prelaundering. Results showed that fabric treated with permethrin at a rate of 0.125 mg/cm2 lost the substance to the skin surface at an average rate of 0.49%/d. At the end of the 7-d exposures in rabbits, about 3.2% of the available permethrin had reached the skin, 2% having been recovered from excreta (absorbed) and 1.2% remaining on the skin surface. Prelaundering the treated fabric had little effect on migration rate, nor did the other variables tested. Exposure dose to humans from wearing permethrin-treated (0.125 mg/cm2) military clothing is predicted to be 6 x 10(-4) mg/kg/d.
79 citations
TL;DR: FA and the mycotoxin are important environmental factors in the pathogenesis of Kashin-Beck disease; and selenium, vitamin C, and vitamin E, which inhibit free-radical formation, are considered to be protective.
Abstract: Kashin-Beck disease (KBD) is a chronic osteoarthritic disease, endemic in parts of China Its etiology is unknown Selenium deficiency, high concentration of organic matter (mainly fulvic acid) in drinking water, and severe contamination of grain by fungi have been proposed environmental causes Free radicals, possible mediators between the environmental factors and origin of KBD, have been studied in this work Drinking water from KBD-affected areas contains a higher level of semiquinone radicals than that from disease-free areas In animal experiments, fulvic acid (FA) accumulated in the skeletal system as semiquinone radicals Contamination of grain by Fusarium oxysporum or Alternaria alternata significantly increased the content of semiquinone radicals Furthermore, corn grown in endemic areas had a higher content of radicals than that from disease-free areas The g factor values for these radicals from contaminated corn were about 20040, in the range of semiquinone radical In monolayer culture of human embryonic chondrocytes, FA and aqueous extracts of grain contaminated by Fusarium injured the chondrocytes and enhanced lipid peroxidation Selenite and superoxide dismutase (SOD) protected the cells from injury by these toxins and reduced lipid peroxide Lower glutathione peroxidase activities and higher levels of lipid peroxidation were also found in the children living in KBD-affected regions Thus, FA and the mycotoxin, which are seen as exogenous free-radical carriers, are important environmental factors in the pathogenesis of Kashin-Beck disease; and selenium, vitamin C, and vitamin E, which inhibit free-radical formation, are considered to be protective
74 citations
TL;DR: The present study validates an experimental model for investigating the toxicokinetics of orally administered mercuric chloride and methylmercuric chloride in mice and major findings using this model are discussed in relation to previous knowledge.
Abstract: Future human exposure to inorganic mercury will probably lead to a few individuals occupationally exposed to high levels and much larger populations exposed to low or very low levels from dental fillings or from food items containing inorganic mercury; human exposure to methylmercury will be relatively low and depending on intake of marine food. Ideally, risk assessment is based on detailed knowledge of relations between external and internal dose, organ levels, and their relation to toxic symptoms. However, human data on these toxicokinetic parameters originate mainly from individuals or smaller populations accidentally exposed for shorter periods to relatively high mercury levels, but with unknown total body burden. Thus, assessment of risk associated with exposure to low levels of mercury will largely depend on data from animal experiments. Previous investigations of the toxicokinetics of mercuric compounds almost exclusively employed parenteral administration of relatively high doses of soluble mercuric salts. However, human exposure is primarily pulmonary or oral and at low doses. The present study validates an experimental model for investigating the toxicokinetics of orally administered mercuric chloride and methylmercuric chloride in mice. Major findings using this model are discussed in relation to previous knowledge. The toxicokinetics of inorganic mercury in mice depend on dose size, administration route, and sex, whereas the mouse strain used is less important. The "true absorption" of a single oral dose of HgCl2 was calculated to be about 20% at two different dose levels. Earlier studies that did not take into account the possible excretion of absorbed mercury and intestinal reabsorption during the experimental period report 7-10% intestinal uptake. The higher excretion rates observed after oral than after intraperitoneal administration of HgCl2 are most likely due to differences in disposition of systemically delivered and retained mercury. After methylmercury administration, mercury excretion followed first-order kinetics for 2 wk, independently of administration route, strain, or sex. However, during longer experimental periods, the increasing relative carcass retention (slower rate of excretion) caused the elimination to deviate from first-order kinetics. Extensive differences in the toxicokinetics of methylmercury with respect to excretion rates, organ deposition, and blood levels were observed between males and females.(ABSTRACT TRUNCATED AT 400 WORDS)
71 citations
TL;DR: It is concluded that hen pheasants are responsive to the overt toxic effects of TCDD and that the lowest cumulative dose of T CDD that produces overt signs of toxicity, 10 micrograms/kg, also reduces egg production and egg hatchability.
Abstract: Hen pheasants (Phasianus colchicus) injected with graded single doses of TCDD (6.25, 25, or 100 micrograms/kg) exhibited delayed-onset body weight loss and mortality--classic signs of the wasting syndrome. The lowest single dose of TCDD to produce this effect was 25 micrograms/kg. When hen pheasants were treated weekly with far lower doses of TCDD (0.01-1.0 microgram/kg/wk) for 10 wk, signs of the wasting syndrome and mortality were also produced. The lowest cumulative TCDD dose required to produce the response, using a weekly dosing regimen, was 10 micrograms/kg. Furthermore, using this dosing regimen, egg production by hens treated with a cumulative TCDD dose of 10 micrograms/kg was reduced, as was hatchability of their eggs. We conclude that hen pheasants are responsive to the overt toxic effects of TCDD and that the lowest cumulative dose of TCDD that produces overt signs of toxicity, 10 micrograms/kg, also reduces egg production and egg hatchability.
63 citations
TL;DR: This analysis demonstrated that the most significant route of human exposure to TCDD is through dermal contact with soil, followed by soil ingestion, fish consumption, and inhalation of airborne particulates, and indicated that soil cleanup standards can be generally higher than those implemented over the past 8 yr.
Abstract: Since the publication of the Times Beach risk assessment in 1984, which suggested that residential soils were of concern when the level of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) was in excess of 1 ppb, there has been continued interest in this topic. Studies conducted within the past 5 yr on the environmental and toxicological behavior of TCDD, as well as refinement of parameters regarding human exposure, indicate that previous assessments of the risk to humans posed by TCDD‐contaminated soil were overestimated. In this paper, recent information drawn from nearly 100 recently published articles regarding the histopathology interpretation of the Kociba bioassay, environmental fate and half‐life of TCDD in soil, and estimates of human exposure via soil ingestion, dermal contact, inhalation, surface runoff, and the consumption of fish were incorporated into a risk assessment. Cleanup levels for TCDD in residential and industrial soils were calculated based on most likely exposure scenarios. Probability d...
62 citations
TL;DR: Using the Microtox method of toxicity assessment designed by Microbics Corporation, the relative toxicities of alachlor, atrazine, and carbofuran, three pesticides commonly used in agricultural production, were determined.
Abstract: Using the Microtox method of toxicity assessment designed by Microbics Corporation, the relative toxicities of alachlor, atrazine, and carbofuran, three pesticides commonly used in agricultural production, were determined. Generally, carbofuran was found to be most acutely toxic, followed closely by atrazine. Alachlor was least toxic of the three pesticides tested. Selected environmental metabolites of these three agri-chemicals were also tested using the same method. Hydroxyalachlor, deethylatrazine, deisopropylatrazine, 3-hydroxycarbofuran, and 3-ketocarbofuran were selected for analysis because previous studies determined their presence in surface and ground-water supplies along with their parents. Results showed that often the metabolites were at least as acutely toxic as their parents, particularly in the case of 3-ketocarbofuran and hydroxyalachlor, which demonstrated toxicities higher or not significantly different than their parents. Hydroxycarbofuran was assessed as the least toxic of all substances tested. The atrazine environmental metabolites were less toxic than their parent.
TL;DR: It is suggested that renal damage due to Cd exposure leads to the decreases in the serum VD level and increases in serum PTH level, and that the more marked changes in serumVD and PTH in the women may play a role in the development of sex-related differences in Cd-induced bone injury.
Abstract: To determine whether depleted serum 1 alpha,25-dihydroxyvitamin D (VD) concentrations are associated with cadmium (Cd)-induced renal damage, the relationships between four indices of renal function and two indicators of bone metabolism, that is, serum VD and parathyroid hormone (PTH) concentrations, were analyzed in 30 male and 44 female subjects exposed to environmental Cd. Also, these associations were compared in male and female subjects to evaluate sex-related differences in vulnerability to the bone damage observed in Cd-exposed persons. Serum VD decreased significantly with declines in creatinine clearance and percentage tubular reabsorption of phosphate, and with increases in serum creatinine and serum beta 2-microglobulin (beta 2m) concentrations in the female subjects exposed to Cd, but not in the male subjects. The correlation between serum VD and PTH levels was also significant only in the females. Correlation coefficients between serum beta 2m and VD and those between serum PTH and VD in both sexes were significantly different. These results suggest that renal damage due to Cd exposure leads to the decreases in the serum VD level and increases in serum PTH level, and that the more marked changes in serum VD and PTH in the women may play a role in the development of sex-related differences in Cd-induced bone injury.
TL;DR: The results suggest that terns are exposed to significantly higher levels of mercury in the northeastern United States than they are in the wintering grounds in South America.
Abstract: Birds are useful indicators of environmental contamination because they are relatively large, conspicuous, top predators in food chains. However, concentrations of contaminants in a bird's tissues reflect the bird's exposure over wide temporal and spatial scales. Birds are most useful as monitors of exposure when these scales are known. In this paper we report concentrations of lead, cadmium, mercury, and selenium in breast feathers of common terns (Sterna hirundo) and roseate terns (S. dougallii) trapped during incubation at breeding colonies in New York and Massachusetts. Terns arrived on the breeding grounds with breast feathers grown on their wintering grounds, and regrew certain feathers that were plucked for analysis. The regrown feathers were themselves plucked, and both sets of feathers were analyzed. For roseate terns at Cedar Beach and common terns at both sites there was a significant increase in mercury levels in the feathers grown on the breeding grounds compared to those grown on the winteri...
TL;DR: Results suggest that acute exposure to near-ambient concentrations of sulfuric acid under conditions that promote the formation of acid as a surface coating in respirable particles can induce a nonspecific airway hyperresponsiveness.
Abstract: Although several epidemiological studies have provided evidence that airborne sulfate particles can produce adverse health effects in susceptible individuals, there is only limited data demonstrating respiratory effects in human volunteers and experimental animals at near ambient concentrations. We have demonstrated previously that the mixing of metal oxide particles with SO2 under humid conditions produces acid‐coated particles that are significantly more potent in causing pulmonary function changes than pure acid droplets. The present study examined the nonspecific airway responsiveness to acetylcholine in guinea pigs exposed to acid‐coated zinc oxide particles. One and a half hours after a 1‐h exposure to the aerosols or a control atmosphere, pulmonary resistance (RL) was measured in awake, spontaneously breathing animals before and during a challenge with increasing doses of iv acetylcholine (Ach). The provocative infusion rate of Ach that resulted in a 100% increase in RL (PR100) was significantly de...
TL;DR: The possibility that in certain localities and cultures sport or subsistence fishermen may consume fish at levels substantially above 200 g/d should be investigated in performing risk assessments, particularly outside the continental United States.
Abstract: Sport or subsistence fishermen sometimes underestimate the risks from eating local fish and distrust authorities regarding potential hazards from fish. We report on lead, cadmium, selenium, and mercury levels in snook, locally called robalo (Centropomus spp.), consumed by local fishermen in Puerto Rico, who ate up to 23 fish/wk. Median levels (in ppb, dry weight) for muscle, adipose, and liver ranged from 683 to 780 for lead, 37 to 600 for cadmium, 50 to 146 for mercury, and 361 to 3986 for selenium. Lead levels were similar in all tissues, and selenium and cadmium levels were highest in the liver. Mercury was higher in muscle than in liver. Computing exposure via ingestion for the average fisherman indicated that if one were to consume robalo throughout the year one would be exposed in excess of the EPA Reference Dose (RfD) for mercury. Using a widely accepted maximum consumption of 200 g/d for fishermen yielded hazard indices (daily consumption/ RfD) below 1 for all four metals, with a value approaching...
TL;DR: Five cases of poisoning by cypermethrin, a pyrethroid pesticide, are presented after the chemical was inadvertently introduced to the air-conditioning ducts and the patients inhaled it.
Abstract: Five cases of poisoning by cypermethrin, a pyrethroid pesticide, are presented. The chemical was inadvertently introduced to the air‐conditioning ducts and the patients inhaled it. Exposed patients experienced shortness of breath, nausea, headaches, and irritability. The exposure was compounded by repeated entry into the contaminated area and slow referral to a physician experienced in pesticide exposures.
TL;DR: BAPN was the most potent inhibitor of the enzyme and a series of primary and substituted aminopropionitriles was studied for their ability to inhibit lysyl oxidase activity both in vitro and in vivo.
Abstract: Inhibition of lysyl oxidase (protein‐lysine 6‐oxidase, EC 1.4.3.13) decreases the rate of collagen and elastin cross‐link formation and produces osteolathyrism in animals. Organic nitriles, including s‐aminopropionitrile (BAPN), have been shown to irreversibly inhibit lysyl oxidase in vitro. Both BAPN and 3,3'‐iminodipropionitrile (IDPN) have been shown to produce osteolathyric changes when administered to animals. To date compounds that have been reported to inhibit this enzyme possess a primary amine functional group. In this study a series of primary and substituted aminopropionitriles was studied for their ability to inhibit lysyl oxidase activity both in vitro and in vivo. Our results show that of the compounds tested, BAPN was the most potent inhibitor of the enzyme. Reversible inhibition of lysyl oxidase in vitro was found with two secondary aminonitriles, IDPN and monomethy‐laminopropionitrile (MMAPN). There was no inhibition of enzyme activity associated with the tertiary compound 3,3'‐dimethylam...
TL;DR: The data bring into question the complete validity of the rhesus monkey model to predict human dermal absorption of the herbicide 2,4-D-amine.
Abstract: Percutaneous absorption of the 14C‐ring‐labeled phenoxy herbicide 2,4‐D‐amine (2,4‐dichlorophenoxyacetic acid dimethylamine) was examined following topical applications of the herbicide to the palm and forearm of human volunteers. The effect of two vehicles (water and acetone) and the mosquito repellent DEET (N,N‐diethyl‐m‐toluamide) on dermal absorption of 2,4‐D‐amine also was investigated. The total percent dermal absorption was calculated from the mean percent urinary recoveries and was not corrected for nonurinary excretion. The data revealed 14 ± 4.5% (standard deviation) and 10 ± 11.5% palmar absorption of 2,4‐D‐amine applied in water, with and without DEET, respectively, and 7 ± 6.2% and 13 ± 5.0% forearm absorption of the herbicide applied in water or acetone, respectively. Soap‐and‐water skin washes conducted at 24 h posttreatment removed up to 34% of the applied dose. Successive tape strips of skin taken at 24 h posttreatment demonstrated generally decreasing herbicide levels in the outer layers...
TL;DR: Surfactant was lost more readily from quartz than from kaolin, with consequent more rapid restoration of mineral surface hemolytic activity for quartz, and implications for determining the mineral surface bioavailability of silica and silicate dusts are discussed.
Abstract: Respirable-sized quartz, a well-established fibrogenic mineral dust, is compared with kaolin in erythrocyte hemolysis assays after treatment with saline dispersion of dipalmitoyl phosphatidylcholine, a primary phospholipid component of pulmonary surfactant. Both dusts are rendered inactive after treatment, but the membranolytic activity is partly to fully restored after treatment with phospholipase A2, an enzyme normally associated with cellular plasma membranes and lysosomes. Phospholipid-coated dusts were incubated for periods of 2-72 h at a series of applied enzyme concentrations, and the adsorbed lipid species and hemolytic activity were quantitated at each time for both dusts. Surfactant was lost more readily from quartz than from kaolin, with consequent more rapid restoration of mineral surface hemolytic activity for quartz. Interactions of surfactant and mineral surface functional groups responsible for the mineral-specific rate differences, and implications for determining the mineral surface bioavailability of silica and silicate dusts, are discussed.
TL;DR: This investigation of the variability of TCDD half-life with percent body fat in 36 Ranch Hand veterans who have two T CDD assay results from serum drawn in 1982 and 1987 found no statistically significant change in half- life with relative changes in percentage of body fat from 1982 to 1987.
Abstract: The half‐life of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD), the contaminant of Agent Orange, has been recently estimated in 36 members of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of Agent Orange in Vietnam, as 7.1 yr with a 90% confidence interval of 5.8–9.6 yr. We investigated the variability of TCDD half‐life with percent body fat in these 36 Ranch Hand veterans who have two TCDD assay results from serum drawn in 1982 and 1987. Using a repeated measures linear model, we found a marginally significant change in half‐life with percentage of body fat (p ‐ .09) and no statistically significant change in half‐life with relative changes in percentage of body fat from 1982 to 1987 (p ‐ .60).
TL;DR: The efficacy of potassium ferrate in cleaning contaminated water shows great potential in application to municipal and industrial waste water.
Abstract: The effects of the application of potassium ferrate to remove possible toxic compounds are presented. Potassium ferrate (K2FeO4) is shown in this work to be an effective means to remove toxic metals and nonmetals from aqueous solution. The toxic material present in water is precipitated from aqueous solution and readily removed. Potassium ferrate removes itself from solution. Discolored contaminated water may be made clear by utilizing potassium ferrate. In addition, turbidities of solutions induced by dissolved substances are eliminated by the action of potassium ferrate. The efficacy of potassium ferrate in cleaning contaminated water shows great potential in application to municipal and industrial waste water.
TL;DR: Based on 10% solubilization of soil-bound Cr(VI) and the results of the statistical analysis of previous threshold studies, a concentration of approximately 350 to 500 ppm Cr( VI) in soil should be sufficiently low to protect virtually all exposed people, including children, from chromium-induced allergic contact dermatitis.
Abstract: At least 200 sites in the United States contain soil with elevated levels of trivalent and hexavalent chromium [Cr(III) and Cr(VI)]. Although the potential cancer hazard posed by airborne Cr(VI) has been the primary concern for these sites, a soil cleanup standard based on the potential elicitation of allergic contact dermatitis has been proposed for sites in Hudson County, N.J. This paper describes the rationale for identifying a soil concentration of Cr(VI) that should not pose an allergic contact dermatitis hazard-even in sensitized persons. A literature review of eight published patch test studies that evaluated the allergic response to potassium dichromate was conducted. These studies were evaluated for clinical and statistical relevance in establishing a threshold dose of Cr(VI) to which no more than 10% of the subpopulation sensitized to chromium would respond, and that would protect at least 99.84% of the general population. Although each of the studies had certain methodological limitations when evaluated against current test methods, the data set proved useful for deriving an estimated threshold. Using computer data-fitting techniques based on truncated lognormal distributions, a weighted mean 10% threshold of approximately 150 ppm potassium dichromate or 54 ppm Cr(VI) was identified for the eight studies. Due to the types of limitations noted for these studies, this threshold is likely to be somewhat conservative. Test results have shown that between 5 and 10% of the Cr(VI) at concentrations less than about 500 ppm are released from a soil matrix into an isotonic saline solution simulating sweat. Using human sweat as the extractant, it has been shown that only 0.1% of the CR(VI) at concentrations of approximately 1,000 ppm are released from a soil matrix into sweat. Based on 10% solubilization of soil-bound Cr(VI) and the results of our statistical analysis of previous threshold studies, a concentration of approximately 350 to 500 ppm Cr(VI) in soil should be sufficiently low to protect virtually all exposed people, including children, from chromium-induced allergic contact dermatitis.
TL;DR: It is concluded that the threshold effect depends on the chemical structure of the flavonoid and the enzyme activity, and low threshold doses for conjugating enzymes may be important for the anticarcinogenicity properties of these compounds.
Abstract: The induction of drug-metabolizing enzymes for different dietary flavonoids has been shown previously. The purpose of this study was to determine the threshold effect of these components. Rats were fed diets containing flavone, flavanone, or tangeretin at different levels (20, 50, 200, 500, and 200 ppm). Flavone induced ethoxyresorufin and pentoxyresorufin dealkylase activities at 500 ppm and arylhydrocarbon hydroxylase at 200 ppm. Epoxide hydrolase and glutathion transferase were increased at 200 ppm. UDP-glucuronyl transferases were enhanced at 20 ppm. Flavanone induced pentoxyresorufin dealkylase and arylhydrocarbon hydroxylase at the greatest level. In contrast, epoxide hydrolase and conjugating enzymes were increased at the lowest dose. Significant induction was seen only for ethoxyresorufin deethylase and UDP-glucuronyl transferase with diets containing 2000 ppm tangeretin. We conclude that the threshold effect depends on the chemical structure of the flavonoid and the enzyme activity. Low threshold doses for conjugating enzymes may be important for the anticarcinogenicity properties of these compounds.
TL;DR: It is concluded that TCDD was more persistent in pheasant hens than in chicks and that egg laying was an important route of elimination in the hen.
Abstract: The T 1/2 for whole-body elimination of [3H]-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) derived radioactivity in ring-necked pheasant hatchlings was 13 d, whereas in adult hen pheasants that were not producing eggs it was 378 d. All TCDD-derived radioactivity in hen tissues was from the parent compound. The oral bioavailability of TCDD in the adult hen pheasant varied with the environmental matrix, with 30% of the dose absorbed from a suspension of earthworms, 33% absorbed from a soil suspension, 41% absorbed from a suspension of paper mill sludge, and 58% absorbed from a suspension of crickets. A cumulative dose of 1.0 micrograms TCDD/kg body weight, administered as weekly doses of 0.1 micrograms/kg for 10 wk, did not adversely affect hen condition or egg production. Under these exposure conditions, hens translocated about 1% of their cumulative TCDD dose to each of the first 15 eggs laid. All of the TCDD-derived radioactivity in the eggs was the parent compound and was confined entirely to the yolk; no TCDD was detected in egg albumin. We conclude that TCDD was more persistent in pheasant hens than in chicks and that egg laying was an important route of elimination in the hen.
TL;DR: Results indicate that the mouse bone marrow micronucleus assay can be used to identify organosulfur components of garlic that inhibit genotoxicity.
Abstract: Diallyl thioethers (DATEs), naturally occurring compounds present in garlic, were investigated for their putative ability to inhibit benzo[a]pyrene‐induced genotoxicity in ICR and C3H strains of mice. The mouse bone marrow micronudeus assay was used as an indicator of in vivo genotoxicity. A dose of 0.67 mmol total DATEs/kg body weight inhibited formation of micronucleated polychromatic erythrocytes (MPCEs) by 24%, and 0.33 mmol DATEs inhibited formation of MPCEs by 45%. Possibly the toxicity of DATEs accounted for less inhibition with the higher dose. Formation of MPCEs were inhibited only slightly by DATEs in C3H mice. These results indicate that the mouse bone marrow micronudeus assay can be used to identify organosulfur components of garlic that inhibit genotoxicity.
TL;DR: The results indicate that, in addition to the differences in physical and chemical properties of the two compounds that will affect absorption, the amount of the chemical absorbed is related inversely to the amounts of washed off.
Abstract: The percutaneous penetration of 2,4‐dichlorophenoxyacetic acid (2,4‐D) and 2,4‐D dimethylamine salt (DMA) was evaluated separately in five male volunteers who participated in both experiments. Urine samples collected for 144 h following dermal applications of 10 mg to the dorsum of the hand (9 cm2) were analyzed for 2,4‐D. Following the acid application, an average of 4.46 ± 0.849% was recovered in the urine and a significantly lower amount of 1.76 ± 0.568% following the DMA application. Significantly higher amounts of 2,4‐D DMA (7.68 ± 0.493 mg) were washed off the hand 6 h following application as compared with 2,4‐D acid (5.35 ± 0.384 mg). These results indicate that, in addition to the differences in physical and chemical properties of the two compounds that will affect absorption, the amount of the chemical absorbed is related inversely to the amount of washed off. Urinary excretion of 2,4‐D was not complete in all volunteers 144 h following either application, but in all cases it was approaching the...
TL;DR: Mercuric chloride treatment for 2 yr clearly exacerbated the severity of the spontaneous nephrotoxicity prevalent in aging F344 rats, and the excessive mortality that occurred in the male rats was probably due to a combination of these factors.
Abstract: Both sexes of F344 rats were gavaged with maximal tolerated doses of mercuric chloride for periods from 2 wk to up to 2 yr to investigate chronic nephrotoxicity and potential carcinogenicity. The toxicity of mercuric chloride was excessive after 2 wk of exposure to doses ranging from 1.25 to 20 mg/kg, compromising renal function by selectively destroying cells of the proximal tubules, and eliciting marked elevations in urinary biomarker enzymes diagnostic for acute renal tubule necrosis. In the 2‐wk studies, urinary alkaline phosphatase and aspartate aminotransferase were most sensitive to renal mercury toxicity among a panel of six enzymes, exhibiting twofold increases above controls at the 5.0 mg/kg dose, before changes in the other enzymes occurred. Urinary lactate dehydrogenase was the most responsive enzyme, with up to 11‐fold increases in activity above controls. In response to mercuric chloride exposure of 5.0 mg/kg for 2–6 mo, the greatest and most persistent increases in elevation of urinary enzy...
TL;DR: It is concluded that TMA exerts teratogenic effects on mouse embryos in culture and inhibits their growth by reducing macromolecular synthesis; these effects may not involve glutathione depletion or generation of free radicals.
Abstract: Trimethylamine (TMA) is an aliphatic amine, and its blood levels can increase after ingestion of certain foods, such as fish, and during disease states, such as chronic renal failure. We recently reported that TMA can inhibit fetal development in vivo and in vitro in mice. The present studies were done to find out if the inhibitory effects of TMA on embryonic development are caused by a decrease in macromolecular synthesis, using mouse embryo cultures as the experimental model. At a submaximally toxic concentration (0.75mM), TMA inhibited the growth of embryos to approximately 70% of control and caused neural‐tube defects in 73% of embryos. By 42 h of culture, DNA, RNA, and protein content of TMA‐treated embryos were approximately 50% of the control values. Embryotoxic effects of TMA were not caused by changes in pH and osmolarity of the culture media. The inhibitory effects of TMA on embryonic growth were time dependent and apparent at 2–4 h of culture. The inhibition of growth was accompanied by a decre...
TL;DR: Of the three compounds examined in this study, only SMD affected thymus weight, spleen weight, and splenic NK cell activity in vivo, and direct measurement of the cytotoxicity of all three compounds toward splenocytes and thymocytes in vitro demonstrated that SMD and EBD are approximately equally potent.
Abstract: Recent studies indicate that sodium methyldithiocarbamate is immunotoxic. Major effects of this compound in female B6C3F1 mice include decreased thymus weight, increased spleen weight, and decreased natural killer (NK) cell activity. The effects of other dithiocarbamates on these parameters are not known, and the immunotoxic potential of this important class of compounds is uncertain. In the present study, the effects of sodium methyldithiocarbamate (SMD), sodium diethyldithiocarbamate (DEDTC), and disodium ethylene‐bis(dithiocarbamate)(EBD) on thymus weight, spleen weight, and NK cell activity were compared in female B6C3F1 mice. SMD caused significant loss of thymic weight following oral administration at 200, 225, or 300 mg/kg/d for 7 d and caused significant suppression of splenic NK cell activity at doses of 150, 225, or 300 mg/kg/d for 7 d. In contrast, a dose of 1000 mg/kg/d of DEDTC was required to decrease significantly thymus weight or increase spleen weight, and the only significant change prod...
TL;DR: The data indicate that MCMV is a useful host resistance model to be applied in immunotoxicity testing when suppression of NK cell activity has been demonstrated, however, virus-augmented activity may be a better indicator than spontaneous activity.
Abstract: The purpose of this study was to determine the relationship between chemical suppression of natural killer (NK) cell activity in mice and chemical effects on susceptibility to murine cytomegalovirus (MCMV) infection. The goal was to provide a rational basis for applying MCMV as a host resistance model for immunotoxicity testing and to provide risk assessors some guidance in relating suppression of NK cell activity to enhanced risk of disease. Data from studies with eight chemicals administered in various doses and by various routes were evaluated, and a significant correlation was observed between chemical suppression of virus-augmented NK cell activity and increased mortality due to MCMV infection. In contrast, effects of the same chemical treatments on spontaneous NK cell activity (i.e., basal activity in uninfected mice) did not correlate with effects of these chemicals on mortality due to MCMV. Although chemicals that suppressed spontaneous NK cell activity enhanced infection, the converse was not always true--that is, increased susceptibility to infection and suppression of virus-augmented NK cell activity were observed on three occasions when spontaneous NK cell activity was unaffected. This latter phenomenon plus the fact that for two chemicals spontaneous NK was suppressed at concentrations twofold below that which affected mortality appear to account for the poor statistical correlation. Nevertheless, the data indicate that MCMV is a useful host resistance model to be applied in immunotoxicity testing when suppression of NK cell activity has been demonstrated. However, virus-augmented activity may be a better indicator than spontaneous activity. The data also indicated that suppression of NK cell activity is predictive of increased susceptibility to infection and hence provides qualitative guidance (hazard identification) to risk assessors.