Martha R. Sumler

Comparison of the penetration of 14 pesticides through the skin of young and adult rats

In vivo percutaneous absorption of 14 pesticides was studied in young (33-d-old) and adult (82-d-old) female Fischer 344 rats, at three different dose levels. Carbon-14-labeled pesticides in acetone were applied to previously clipped middorsal skin. The treatment area was 2-3% of the body surface area. Penetration of the pesticides during a 72-h period ranged from approximately 1%-90%, depending on compound, dose, and age of animal. No clear age-related pattern of dermal absorption among compounds was found. Only chlordecone, folpet, and permethrin did not show significant age-dependent differences in skin penetration. Atrazine, carbaryl, chlorpyrifos, and hexachloro-biphenyl had greater absorption in the young, while carbofuran, captan, dinoseb, DSMA, MSMA nicotine, and parathion displayed greater absorption in the adult. The majority of the compounds showed dose-dependent penetration. The dose-response curves for penetration were not parallel for 8 of the 14 compounds studied.

Sexual differences in the distribution and retention of organic and inorganic mercury in methyl mercury-treated rats

At 56 days of age, male and female Long-Evans rats received 1 mumole of 203Hg-labeled methyl mercuric chloride per kilogram sc and total, organic, and inorganic mercury contents and concentrations in tissues were determined for up to 98 days postdosing. Whole body clearance of mercury was faster in females than in males, and females attained higher peak percentages of the methyl mercury dose in kidney and brain than did males. Females had significantly higher mean percentages of the mercury dose present in the kidney and brain as organic or total mercury and in brain as inorganic mercury than did males. Males had significantly higher mean percentages of the dose present as organic or total mercury in pelt and whole body than did females. When expressed on a concentration basis, the only significant sexual difference was in the higher average concentration of organic mercury in the kidneys of females. When expressed on a tissue content basis, significant male-female differences in the kinetics (sex X time interactions) of organic mercury retention were found in kidney, brain, skeletal muscle, pelt, and whole body. Significant sex X time interactions in the concentrations of organic mercury were found in kidney, skeletal muscle, and whole body. Kinetics of retention and concentration of inorganic Hg in the pelt differed significantly for males and females. Discordance in degree of statistical significance of differences in mercury contents and concentrations reflected in part differences in relative body composition of males and females. Integrated exposures of tissues of males and females to organic or inorganic mercury were determined by fitting multiexponential retention functions to retention data. Differences in integrated exposure were estimated by the female-to-male ratio of areas under retention curves. Reconstruction of whole body organic and inorganic mercury burdens from constituent tissues indicated that integrated exposures of males and females to inorganic mercury were equal but females had a lower integrated exposure to organic mercury. Integrated exposure of liver to either form of mercury was about equal in males and females. However, the integrated exposure of the brain of females to inorganic mercury was 2.19 times that of males suggesting a sexual difference in accumulation or retention of inorganic mercury in the nervous system. These sexual differences in distribution and retention of organic and inorganic mercury after methyl mercury exposure may underlie reported sexual differences in sensitivity to the toxic effects of methyl mercury.

Sexual differences in the excretion of organic and inorganic mercury by methyl mercury-treated rats

Adult male and female Long Evans rats received 1 mumole of methyl (203Hg) mercuric chloride per kilogram sc. Whole-body retention of mercury and excretion of organic and inorganic mercury in urine and feces were monitored for 98 days after dosing. Females cleared mercury from the body more rapidly than did males. The major route of mercury excretion was feces. By 98 days after dosing, cumulative mercury excretion in feces accounted for about 51% of the dose in males and about 54% of the dose in females. For both sexes, about 33% of the dose was excreted in feces as inorganic mercury. Cumulative excretion of organic mercury in feces accounted for about 18 and 21% of the dose in males and females, respectively. Urinary excretion of mercury was quantitatively a smaller route for mercury clearance but important sexual differences in loss by this route were found. Over the 98-day experimental period, males excreted in urine about 3.2% of the dose and females excreted 7.5%. Cumulative organic Hg excretion in urine accounted for 1.8% of the dose in males and 5.3% of the dose in females. These sexual differences in urinary and fecal excretion of organic and inorganic mercury following methyl mercury treatment were consistent with previous reports of sexual differences in mercury distribution and retention in methyl mercury-treated rats, particularly sexual differences in organic mercury uptake and retention in the kidney. Relationships between body burdens of organic or inorganic Hg and output of these forms of Hg in urine and feces were also found to be influenced by the interval after MeHg treatment and by sex. Relationship between concentration of Hg in liver and feces and in kidney and urine differed for organic and inorganic Hg and depended upon sexual status and interval after MeHg treatment. These findings emphasize that sexual differences in distribution, retention, and metabolism of methyl mercury are factors to be considered in estimations of hazards associated with exposure to this agent.

Age-related percutaneous penetration of 2-sec-butyl-4,6-dinitrophenol (dinoseb) in rats.

[14C]Dinoseb was applied to previously clipped back skin of 33- and 82-day-old female Fischer 344 rats at a dosage range of 210-2680 nmol/cm2. Radioactivity in the treated skin, tissues, urine, and feces was determined at 1, 6, 24, 48, 72, and 120 hr following dermal application. In vitro dermal absorption of [14C]dinoseb was also measured in rats of the same age by static and flow-through methods. In vivo dermal absorption in both young and adults appeared biphasic with 55.6 and 82.7% of the recovered dose, respectively, penetrating in 72 hr. In vitro measurements of skin absorption at 72 hr with static cells showed higher values in young and lower values in the adult compared to in vivo dermal absorption values. In vitro flow-through measurements at 72 hr gave lower dermal absorption values for both young and adult rats, compared to in vivo values. Following in vivo application, adults excreted about 70% of the total recovered dose in urine, 16% in feces, and retained 7% in the body at 120 hr. HPLC analysis of urine collected at 24 hr from adults administered [14C]dinoseb showed extensive metabolism of parent. Excretion and retention results for young were about 80% of the adult values, which also was the young to adult ratio of dermal penetration. Blood had the highest concentration of dinoseb-derived radioactivity of the tissues examined. The kidney to blood ratio averaged 0.60 in young and 0.41 in adults, while the liver and carcass to blood ratio averaged 0.18 in young and 0.11 in adult. Dermal absorption in young rats was slightly less than that in adults, and the subsequent kinetics of retention and excretion appeared different. In vitro dermal penetration of dinoseb was usually lower than in vivo absorption.

Dermal penetration of [14C] captan in young and adult rats

Age dependence in dermal absorption has been a major concern in risk assessment. Captan, a chloroalkyl thio heterocyclic fungicide, was selected for study of age dependence as representative of this class of pesticides. Dermal penetration of [14C]captan applied at 0.286 mumol/cm2 was determined in young (33-d-old) and adult (82-d-old) female Fischer 344 rats in vivo and by two in vitro methods. Dermal penetration in vivo at 72 h was about 9% of the recovered dose in both young and adult rats. The percentage penetration was found to increase as dosage (0.1, 0.5, 2.7 mumol/cm2) decreased. Two in vitro methods gave variable dermal penetration values compared with in vivo results. A static system yielded twofold higher dermal penetration values compared with in vivo results for both young and adult rats. A flow system yielded higher dermal penetration values in young rats and lower penetration values in adults compared with in vivo results. Concentration in body, kidney, and liver was less in young than in adult rats given the same absorbed dosage. A physiological pharmacokinetic model was developed having a dual compartment for the treated skin and appeared to describe dermal absorption and disposition well. From this model, tissue/blood ratios of captan-derived radioactivity for organs were found to range from 0.35 to 3.4, indicating no large uptake or binding preferences by any organ. This preliminary pharmacokinetic model summarizes the experimental findings and could provide impetus for more complex and realistic models.

Distribution and retention of organic and inorganic mercury in methyl mercury-treated neonatal rats

Seven-day-old Long Evans rats received one mumol of 203Hg-labeled methyl mercury/kg sc and whole body retention and tissue distribution of organic and inorganic mercury were examined for 32 days postdosing. Neonates cleared mercury slowly until 10 days postdosing when the clearance rate abruptly increased. During the interval when whole body clearance of mercury was extremely slow, methyl mercury was metabolized to inorganic mercury. Peak concentration of mercury in kidney occurred at 2 days postdosing. At 32 days postdosing, 8% of mercury in kidney was in an organic from. Liver mercury concentration peaked at 2 days postdosing and organic mercury accounted for 38% at 32 days postdosing. Brain concentrations of mercury peaked at 2 days postdosing. At 10 days postdosing, organic mercury accounted for 86% of the brain mercury burden, and, at 32 days postdosing, for 60%. The percentage of mercury body burden in pelt rose from 30 to 70% between 1 and 10 days postdosing. At 32 days postdosing pelt contained 85% of the body burden of mercury. At all time points, about 95% of mercury in pelt was in an organic form. Compartmental analysis of these data permitted development of a model to describe the distribution and excretion of organic and inorganic mercury in methyl mercury-treated neonatal rats.

Dermal penetration of carbofuran in young and adult fischer 344 rats

Dermal penetration of carbofuran was determined in young (33 d) and adult (82 d) female Fischer 344 rats employing in vivo and in vitro methods. In vivo dermal penetration at 120 h was 43% for young and 18% for adult rats. The half-time for carbofuran skin penetration (in vivo) was 128 h for the young and 400 h for the adults. The young to adult ratio of dermal penetration was greater than 1 at all time points (average 2.9) and had a maximum of 4.2 at 24 h. Cumulative urinary excretion approached about 95% of the absorbed dose in both the young and adult animals at 120 h. Whole-body retention was slightly higher in adults. Kidney showed the highest tissue-to-blood concentration ratio (4.6 in adult, 2.3 in young). The ratio for the carcass was 2.8 in the adult and 2.4 in the young. The urine/blood concentration ratio was high, 435 in the adult and 573 in the young. The feces/blood ratio was 44 in the adult and 65 in the young. Skin absorption by the in vitro continuous-flow system was 41% for the young and 11% for the adult at 72 h, compared to 36% and 13% by the in vivo method. The static in vitro method gave consistently lower skin penetration values of 12% for the young and 8.8% for the adult. Differences in the kinetics of retention and excretion were observed between the young and adult animals.

Dermal absorption and disposition of 1,3‐diphenylguanidine in rats

Dermal absorption, distribution, and metabolism of 1,3-diphenylguanidine (CAS 102-06-7) (DPG), widely used as an accelerator in processing rubber and in food packaging, was studied in adult female Sprague-Dawley rats. DPG shows 10% penetration through clipped back skin of the rats in 5 d. The first-order dermal absorption rate constant as determined by least square method was 0.021 +/- 0.002 d-1 (T1/2 = 33.6 d). Approximately 13% of the absorbed dose remained in the body in 5 d. Retention in skin, muscle, liver, intestine and fat contributed most to the body burden of DPG-derived radioactivity in 5 d. All tissues showed tissue to blood ratios greater than 1, with liver and intestine ratios of 26 at 5 d. Approximately 61% of the absorbed dose was eliminated into urine and 27% into feces in 5 d showing rapid clearance of absorbed DPG from the body. High-pressure liquid chromatography (HPLC) analysis of urine revealed two major peaks [parent compound and metabolite(s)]. Within 72 h, approximately 50% of the DPG-derived radioactivity excreted in the urine was parent compound. After 72 h, the DPG-derived radioactivity in the urine was present in the form of a single metabolite, and no parent compound was detected. No parent compound was detected in feces. Two metabolites, neither of which occurred in urine, were detected in feces. The HPLC analysis of the radioactivity at the application site showed only parent compound. Even though DPG shows slow dermal penetration, this route of exposure needs to be considered in the risk assessments because of the suspected chronic toxicity of DPG.