Acetone Vehicle Research Articles

POLYCHLORINATED BIPHENYLS ARE SELECTIVELY NEUROTOXIC IN THE DEVELOPING SPISULA SOLIDISSIMA EMBRYO

Polychlorinated biphenyls (PCBs) are ubiquitous environmental pollutants that accumulate to toxic levels in the food chain. Using Spisula solidissima (surf clam) embryos as a developmental model, it was shown that Aroclor 1254 specifically targets two neuronal structures during embryonic development. Embryos were exposed to 1, 10, or 100 ppm Aroclor 1254 or an acetone vehicle control posthatching for 24, 48, and 72 h. Embryos labeled with a serotonin antibody or a neural antigen antibody and a rhodamine-conjugated secondary antibody were viewed by confocal microscopy. The cerebropleural ganglion showed a decrease both in serotonin production and in the size of the serotonin-synthesizing region upon exposure to 10 and 100 ppm Aroclor 1254. These decreases were detectable as early as 48 h postfertilization. When exposed to 100 ppm Aroclor 1254, the primitive neural plexus, which coordinates the movements of the mouth and velum, showed a delay in onset and cessation of expression of a molluscan-specific neural antigen. Exposure to Aroclor 1254 did not affect the overall growth and morphology of the embryos. In addition, analyses of total protein profiles and heat-shock protein 70 levels showed that exposure to Aroclor 1254 did not trigger protein degradation or cause a stress or shock response. These results show that exposure of Spisula embryos to Aroclor 1254 specifically targets neurogenesis while having no effect on the overall growth of the embryo.

Accessory cell populations in draining lymph nodes of lambs in the elicitation phase of DNCB-induced contact hypersensitivity

The effect of experimentally induced contact hypersensitivity on accessory cell populations in draining lymph nodes of lambs was studied. Previous studies of draining lymph nodes of lambs during the elicitation phase of CHS have shown that there are significant changes in T-cell subpopulations, particularly CD4 + cells and γδ T-cells, but the behaviour of accessory (antigen presenting) cell populations was not investigated. The immunohistochemical presence of accessory cell populations was determined using markers for CD68, Pan MHCII, MHCII DQ, MHCII DR, OvCD1w1 (putative human CD1a/c-like) and OvCD1w2 (human CD1b-like). Ten lambs were sensitised, and 14 days later re-challenged, by applying the hapten di-nitro-chloro-benzene (DNCB) together with an acetone and olive oil (AOO) vehicle, onto the skin. Cryosections of the draining lymph nodes were stained immunohistochemically for the accessory cell markers. Using an image analysis system, the areas of staining in the lymph nodes from the challenged animals were compared with measurements in control animals. A significant increase in staining for CD68 + cells was detected in the cortex of the DNCB-treated group ( p=0.003). A significant increase in staining for the Pan MHCII marker was also observed in the DNCB group ( p=0.013). These results show that MHCII + cells and CD68 + cells constitute a prominent cell population in the cortex of the regional lymph nodes of lambs in the late elicitation phase of DNCB-induced contact hypersensitivity.

A multihit, multistage model of chemical carcinogenesis.

Carcinogenesis involves the accumulation of genetic changes within a single cell. Tumor promotion functions in the initial clonal expansion of an initiated cell but is generally not considered to influence later stages. To investigate whether tumor promotion can influence later stages of carcinogenesis we developed a two-hit 7, 12-dimethylbenz[a]anthracene (D) protocol designed to enrich for keratinocytes that contain at least two D-induced genetic alterations. FVB/N mice were initiated with D and promoted with 12-O-tetradecanoylphorbol-13-acetate (T) or treated with acetone (A) vehicle for 6 weeks. At 7 weeks after the start of promotion, but before visible papilloma development, groups of mice were treated with a second dose of D or A and 1 week later T promotion was resumed. D/T/A/T mice developed 2.8 papillomas/mouse and D/A/D/T mice demonstrated an additive tumor response and developed 5.8 papillomas/mouse. Importantly, D/T/D/T mice developed 12.4 papillomas/mouse, thereby demonstrating a synergistic tumor response compared with D/A/D/T and D/T/A/T mice. D/T/D/T papillomas exhibited increases in suprabasal S phase cells and keratin 13 expression when compared with D/T/A/T papillomas. D/T/D/T mice developed squamous cell carcinomas (SCCs) 10 weeks earlier than D/T/A/T mice and demonstrated a 96% malignancy incidence and 1.71 SCC/mouse compared with D/T/A/T mice, which demonstrated a 28% malignancy incidence and 0.32 SCC/mouse. Greater than 90% of D/T/A/T and D/T/D/T papillomas and SCCs contained mutant Ha-ras, while a normal Ha-ras allele persisted in all cases, indicating that a gene other than the remaining normal allele of Ha-ras was a target gene for the second D hit. These data demonstrate that: (i) promotion between the first and second hits has a profound outcome on carcinogenesis, presumably by increasing the probability that a second hit will occur in a previously initiated cell; (ii) continued promotion after the second hit is required for full expression of malignancy; (iii) the classic initiation-promotion protocol can be extended to a multihit, multistage model.

Neuropeptide Denervation Alters Both the Elicitation and Induction Phases of Contact Hypersensitivity in Mice

The effects of permanent disruption of neuropeptide transmission on the induction (i.e., sensitization) and elicitation (i.e., challenge) phases of contact hypersensitivity (CHS) are described. BALB/c mice were chemically denervated of neuropeptide (i.e., tachykinin) containing sensory C fibers by an acute injection of capsaicin (50 mg/kg) on postnatal day (PND) 2 to 3. As young adults (PND 45–60), these mice and their control littermates were sensitized by topical application of 0.1% 2,4-dinitrofluorobenzene (DNFB) or vehicle. Treatment groups generated from this exposure regimen consisted of untreated, controls (O/O), denervated, controls (CAP/O), untreated, sensitized (O/DNFB), and denervated, sensitized (CAP/DNFB). The elicitation phase of CHS was evaluated in these animals by measuring ear thickness in response to a DNFB challenge. In DNFB-sensitized groups, ear thickness was significantly increased over controls but was additionally increased 2.4-fold in CAP/DNFB compared to O/DNFB mice. The induction phase of CHS was next assessed in young adult mice by measuring lymph node cell (LNC) proliferation. For this, mice were sensitized for 3 consecutive days before their draining, auricular nodes were removed. The LNC were dissociated and cultured for 24 h with tritiated thymidine to assess LNC proliferation. As expected, significantly higher numbers of LNC occurred in both DNFB-sensitized groups (CAP/DNFB, O/DNFB) compared to the unsensitized, controls (CAP/O, O/O). However, LNC proliferation in CAP/DNFB was significantly higher than O/DNFB animals. Flow cytometry on similarly exposed mice failed to demonstrate any significant difference in the population of CD4CD8 or CD3CD45R LNC cells from neuropeptide-denervated (CAP/O, CAP/DNFB) mice or their respective treatment mates (O/O, O/DNFB), suggesting that alterations in T or B cell populations did not underlie these changes. Finally, cytokine release from the LNC from these treatment groups was examined. For this, the auricular lymph nodes were removed from animals, 2 to 4 h after the animals were administered a single application of a sensitizing concentration (0.1%) of DNFB or acetone vehicle. LNC, dissociated from these nodes, were cultured for 24 h. The nutrient media was removed from these cultured cells and examined for the release of proinflammatory cytokines, interleukin (IL)-1β, IL-2 and tumor necrosis factor (TNF)α, by ELISA. There were no significant increases in IL-2. However, IL-1β release was significantly increased in CAP/DNFB mice over O/DNFB by 18-fold and by over 30-fold compare to O/O controls. Levels of TNFα were significantly increased in both O/DNFB and CAP/DNFB mice over the nonsensitized controls (O/O, CAP/O). CAP/DNFB values were approximately double that of O/DNFB. There was no significant difference in IL-1β or TNFα release between the nonsensitized controls (O/O, CAP/O). Collectively, these data indicate that neuropeptide denervation by neonatal administration of capsaicin alters both the induction and elicitation phases CHS and may modify sensitivity to chemically induced CHS.

Tripropylene glycol diacrylate but not ethyl acrylate induces skin tumors in a twenty-week short-term tumorigenesis study in Tg.AC (v-Ha-ras) mice.

The toxicity of the esters of acrylic acid are poorly understood even though significant human exposure occurs. To conduct rapid comparative short-term bioassays, we used the Tg.AC (v-Ha-ras) transgenic mouse model to determine the toxicity and potential carcinogenicity of tripropylene glycol diacrylate (TPGDA) alone and in a reference formulated ultraviolet radiation curable lacquer (Lacquer A), which is used in the ultraviolet radiation curable surface coatings. For comparison, ethyl acrylate (EA) was used as a reference acrylate. Insertion of the zeta-globin promoted v-Ha-ras transgene into the FVB mouse genome (Tg.AC) introduced a defined genetic lesion, which is critical but insufficient by itself to induce benign or malignant tumors in the skin unless activated. Activation and expression of the transgenic ras oncoprotein in this mouse line induces a dose-related increase in papillomas (skin reporter phenotype) within weeks. Based on dose-related increases in skin hyperplasia following dermal exposure to EA, TPGDA, or Lacquer A (applied equimolar for TPGDA concentration), the dosing regimen was selected. Starting at 12 wk of age, the agents were administered topically (200 microliters of acetone vehicle) 3 times/wk for 20 wk to the shaved dorsal skin of female Tg.AC mice (n = 10/group). TPGDA and reference Lacquer A (equimolar for TPGDA) at 5 or 10 mumoles/mouse but not EA (60, 300, or 600 mumoles/mouse) or TPGDA or Lacquer A at 1 mumole/mouse induced a dose-related increase in papillomas between 6 and 12 wk of treatment that reached a maximum number of papillomas per mouse between 19 and 20 wk of treatment. These results indicate that TPGDA is significantly more potent than EA for inducing the skin reporter phenotype and may be predicted to be carcinogenic in long-term cancer bioassays at the site of contact.

In vitro percutaneous penetration of methyl-parathion from a commercial formulation through the human skin.

OBJECTIVE: To compare in vitro percutaneous absorption of methyl-parathion dissolved in an acetone vehicle and in the form of a commercial formulation. METHODS: Penetration through the human skin was measured...

Time- and dose-dependent biom arker responses in flounder (Platichthys flesus L.) exposed to benzo[a]pyrene, 2,3,3′,4,4′, 5-hexachlorobiphenyl (PCB-156) and cadmium

Responses in flounder (Platichthys flesus) towards benzo [a]pyrene (BaP), 2,3,3′,4,4′,5-hexachlorobiphenyl (PCB-156), and cadmium (Cd) were investigated in time-course and dose-response studies of selected biomarkers. Measurements of biliary fluorescent BaP metabolites and hepatic concentrations of PCB-156 and cadmium showed that the injected toxicants were rapidly m obilized from the muscle to the liver, but a depot effect was indicated in the highest dose groups of BaP and PCB-156 (12 mg kg-1 bodyweight). Clearest biomarker responses were found in the induction of hepatic cytochrome P450 1A (CYP1A) enzymes as a response towards BaP and PCB-156 exposure. Maximum induction of CYP1A dependent 7-ethoxyresorufin O-deethylase (EROD) activity was observed after 2 and 8 days in BaP and PCB-156-treated flounder, respectively. Positive dose-effect relationships were observed towards both compounds, but the CYP1A induction was more persistent with PCB exposure than with BaP exposure. In Cd-exposed fish, the hepatic level of metallothionein responded more slowly with highest levels observed after 16 days in the time-study. In the combined BaP + Cd treatment, the CYP1A induction was only slightly suppressed. Aspartate aminotransferase in serum appeared to be responsive towards BaP, but also towards the acetone vehicle in controls in the first part of the exposure period. Hematocrit as well as hepatic activities of aldrin epoxidase, glutathione S-transferase, and UDP-glucuronyl transferase were not responsive to any treatm ent in the present study. In general, the results demonstrate that selected biom arkers in flounder are responsive to PAH, PCB, and heavy metal pollutant exposure, indicating the applicability of this species in future environmental pollution monitoring programmes.

PERCUTANEOUS ABSORPTION OF 2,4-DICHLOROPHENOXYACETIC ACID FROM SOIL WITH RESPECT TO SOIL LOAD AND SKIN CONTACT TIME: IN VIVO ABSORPTION IN RHESUS MONKEY AND IN VITRO ABSORPTION IN HUMAN SKIN

The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), used for control of weeds in agriculture, forestry, and rights of way, can accumulate as a residual chemical in soil. The objective was to determine percutaneous absorption of 2,4-D from soil, with emphasis on soil load and skin contact time. With control acetone vehicle, in vivo absorption of 2,4-D in the rhesus monkey was 8.6 +/- 2.1% of the dose, which compared closely to published human absorption of 6.0 +/- 2.4%. Percutaneous absorption from soil loads of 1 and 40 mg/cm2 were 9.8 +/- 4.0 and 15.9 +/- 4.7%, respectively, values similar to acetone vehicle. In vitro absorption in human skin calculated from skin contact accumulation over 24 h was 1.8 +/- 1.7, 1.7 +/- 1.3, and 1.4 +/- 1.2% for soil loads of 5, 10, and 40 mg/cm2, respectively. Thus, soil load did not affect 24-h percutaneous absorption. Current Environmental Protection Agency (EPA) recommended calculated reductions due to soil load are not supported by these results with 2,4-D. Percutaneous absorption of 2,4-D from acetone vehicle for 8 h dosing period was 3.2 +/- 1.0%, one-third the value of 8.6 +/- 2.1% over 24 h. With soil vehicle, absorption for 8 h was only 0.03 +/- 0.02% for 40 mg/cm2 soil load and 0.05 +/- 0/.004% for 1 mg/cm2 soil load. Absorption for 16 h was 2.2 +/- 1.2%. Absorption over time was linear for acetone vehicle, where total dose is deposited on skin, but not linear for soil vehicle, which had an 8-h delay (lag time). This equates with a normal 8-h work day where most of the contaminated soil can be washed off the skin. The apparent partition coefficient of 2,4-D between soil and water changed over time. This suggests there is a "mobility" phase for 2,4-D in soil that will change with time. For soil vehicle, percutaneous absorption of 2,4-D was not linear in respect to soil load or to skin contact time. Calculation based on assumed linearity can falsely estimate potential human health hazard. Clearly, the dermatokinetics with soil and skin represent complex interactive forces that require detailed evaluation before overgeneralizing rules for interpretation in terms of risk assessment.

Lysosomal membrane responses in the blood and digestive cells of mussels experimentally exposed to fluoranthene

In order to determine if cellular responses to contaminant exposure differed between cell types, from within the same host, neutral red retention (NRR) was used as a determinant of lysosomal membrane damage in blood and digestive cells isolated from Mytilus edulis exposed in vivo to the model hydrocarbon fluoranthene. In addition, the sensitivity of NRR as a biomarker of contaminant effect for isolated digestive cells, was compared to that of lysosomal latency, as an established biomarker of lysosomal damage, in tissue sections of digestive gland. The results of the NRR assay indicated a significant depression in the dye retention time following exposure to fluoranthene, and to its acetone vehicle, which was indicative of membrane failure. There was, however, no significant difference between the lysosomal retention times for the two cell types under investigation indicating a contaminant effect that is independent of the complement of the acid hydrolases within the lysosomes, and possibly their role within a particular cell type, and more toward a failure in a common controlling factor. The comparison of NRR and latency for digestive cell lysosomes, following fluoranthene exposure, showed that there was good agreement between the tests in terms of their ability to demonstrate a detrimental contaminant effect. The latency test, however, failed in contrast to the NRR assay to detect any effect resulting from exposure to the acetone vehicle alone.

Subchronic dermal toxicity study of triethanolamine in C3H/HeJ mice

Triethanolamine (TEA) was applied to the skin of male and female C3H mice (15 per sex per dose group) three times weekly for 95 days (37 applications). TEA was administered at concentrations of 0 (acetone vehicle), 10, 33 and 100% (undiluted) in a volume of 50 μl. The approximate daily doses of TEA were 0.14, 0.46 or 2.0 g/kg per male and 0.16, 0.54 or 2.3 g/kg per female, respectively. The animals were weighed weekly and observed for clinical signs including skin irritation. 10 mice per sex per dose group were designated for clinical chemistry and haematology at terminal killing. Complete autopsies were performed, and the liver, kidneys, brain, heart, spleen, thymus and testes were weighed. Histopathology was performed on tissues from control and high-dose mice and on target organs. Treatment-related effects were limited to a slight epidermal hyperplasia at the site of application at all TEA concentrations. The results indicate that TEA caused a mild local reaction at all concentrations tested, but did not cause systemic toxicity under these conditions.

Characterization of esterase and alcohol dehydrogenase activity in skin. Metabolism of retinyl palmitate to retinol (vitamin A) during percutaneous absorption.

Retinyl palmitate, a widely used ingredient in cosmetic products, is promoted for its beneficial effects on the appearance of skin. Previous studies suggest that enzymes are available in skin to metabolize this ingredient during skin absorption. Esterase activity hydrolyzes retinyl palmitate to retinol (vitamin A), which is oxidized in many tissues to retinoic acid primarily by alcohol dehydrogenase. The activities of esterase and alcohol dehydrogenase were characterized in hairless guinea pig skin by using flow-through diffusion cells and radiolabeled model compounds (methyl salicylate and benzyl alcohol) previously shown to be metabolized by these enzymes. Methyl salicylate was hydrolyzed by esterase to a greater extent in viable skin than in nonviable skin. Glycine conjugation of salicylic acid and benzoic acid occurred only in viable skin. The metabolism of methyl salicylate and benzyl alcohol occurred to a greater extent in male guinea pig skin than in female guinea pig skin. The percutaneous absorption of both radiolabeled compounds was similar in viable and nonviable skin. About 30 and 18% of topically applied retinyl palmitate were absorbed from an acetone vehicle by hairless guinea pig skin and human skin, respectively. Less than 1% of the applied dose of this lipophilic compound diffused from skin into the receptor fluid. Retinol was the only detectable metabolite of retinyl palmitate in both hairless guinea pig and human skin. In human skin, 44% of the absorbed retinyl palmitate was hydrolyzed to retinol. The use of retinyl palmitate in cosmetic formulations may result in significant delivery of retinol into the skin.

Percutaneous absorption of diazinon in humans

Diazinon is an organophosphorus insecticide which, through general use, comes into contact with human skin. To investigate its percutaneous absorption, human volunteers were exposed for 24 hr to 14C-labelled diazinon applied in acetone solution (2 μg/cm 2) to the forearm or abdomen, or in lanolin wool grease (1.47 μg/cm 2) to the abdomen. Complete void urine samples were collected daily for 7 days. Percutaneous absorption ranged from 2.87 ± 1.16% (mean ± SD, n = 6) to 3.85 ± 2.16% of the applied dose, and there were no statistically significant differences with regard to site or vehicle of application. In rhesus monkeys, over the 7 days after iv dosing (2.1 μCi[ 14C]diazinon, 31.8 μg) a total of 55.8 ± 6.8% (n = 4) of the dose was excreted in the urine, and 22.6 ± 5.2% was eliminated in the faeces (78.4% total accountability). In in vitro percutaneous absorption studies with human abdominal skin, 14.1 ± 9.2% of the applied dose accumulated in the receptor fluid over 24 hr of exposure to 0.25 μg/cm 2 (acetone vehicle). The calculated mass absorbed was the same (0.035 μg/cm 2) for both in vitro and in vivo absorption through human skin.

Percutaneous Absorption of Pentachlorophenol from Soil

Pentachlorophenol (PCP) is one of the most heavily used pesticides. About 80% of PCP is used for wood preservation, whereas the remainder is used as an herbicide, fungicide, and disinfectant. PCP is a probable human carcinogen, based on animal studies. Illness and death have been reported where PCP is in direct contact with skin. PCP is the most ubiquitous compound found when the general population is screened for pesticide residue. PCP is found in soil as well as other environmental sources. Our objective was to determine the skin bioavailability of PCP from soil and from the control vehicle acetone. In vivo in the Rhesus monkey, percutaneous absorption of PCP was 24.4±6.4% of applied dose from soil and 29.2±5.8% of applied dose from acetone vehicle for a 24-hr exposure period. This amount of absorption makes PCP one of the more extensively absorbed compounds to date. Additionally, the 14C half-life was 4.5 days following both intravenous and skin administration of [14C]PCP. These data suggest high bioavailability and an extended biological interaction period with the long half-life. In vitro percutaneous absorption with human cadaver skin and human plasma receptor fluid underestimated the in vivo absorption. Receptor fluid accumulation was 0.6±0.09% and 1.5±0.2% for two skin sources for PCP in acetone vehicle and 0.01±0.00% and 0.00±0.08% for two skin sources with soil vehicle. Skin content after skin surface wash ranged from 2.6 to 3.7% for acetone vehicle and 0.07–0.11% for soil vehicle. Overall accountability for in vitro dose ranged from 81 to 96%.

Percutaneous Absorption of Pentachlorophenol from Soil

Percutaneous Absorbtion of Pentachlorophenol from Soil. Wester, R. C., Maibach, H. I., Sedik, L., Melendres, J., Wade, M., and DiZio, S. (1993). Fundam. Appl. Toxicol. 20, 68-71. Pentachlorophenol (PCP) is one of the most heavily used pesticides. About 80% of PCP is used for wood preservation, whereas the remainder is used as an herbicide, fungicide, and disinfectant. PCP is a probable human carcinogen, based on animal studies. Illness and death have been reported where PCP is in direct contact with skin. PCP is the most ubiquitous compound found when the general population is screened for pesticide residue. PCP is found in soil as well as other environmental sources. Our objective was to determine the skin bioavailability of PCP from soil and from the control vehicle acetone. In vivo in the Rhesus monkey, percutaneous absorption of PCP was 24.4 ± 6.4% of applied dose from soil and 29.2 ± 5.8% of applied dose from acetone vehicle for a 24-hr exposure period. This amount of absorption makes PCP one of the more extensively absorbed compounds to date. Additionally, the 14 C half-life was 4.5 days following both intravenous and skin administration of [ 14C]PCP. These data suggest high bioavailability and an extended biological interaction period with the long half-life. In vitro percutaneous absorption with human cadaver skin and human plasma receptor fluid underestimated the in vivo absorption. Receptor fluid accumulation was 0.6 ± 0.09% and 1.5 ± 0.2% for two skill sources for PCP in acetone vehicle and 0.01 ± 0.00% and 0.00 ± 0.08% for two skin sources with soil vehicle. Skin content after skill surface wash ranged from 2.6 to 3.7% for acetone vehicle and 0.07-0.11% for soil vehicle. Overall accountability for in vitro dose ranged from 81 to 96%.

Percutaneous absorption of [14C]chlordane from soil.

The objective was to determine percutaneous absorption of chlordane in vitro and in vivo from soil into and through skin. The data are needed to calculate the absorbed dose of chlordane from soil, which is then used to assess the toxicity risk. Chlordane, an insecticide for which residues exist in soil, is restricted currently to use for termite control. Chlordane is highly lipophilic with little or no movement out of soil. Soil (Yolo County 65-California-57-8; 26% sand, 26% clay, 48% silt, 0.9% organic) was passed through 10-, 20-, and 48-mesh sieves. Soil then retained by 80-mesh was mixed with 14C-labeled chemical at 67 ppm. Acetone solutions were prepared for comparative analysis. Human cadaver skin was dermatomed to 500 microns and used in glass diffusion cells with human plasma as the receptor fluid (3 ml/h flow rate) for a 24-h skin application time. Chlordane concentration within skin from in vitro studies was 0.34 +/- 0.31% from soil and 10.8 +/- 8.2% from acetone vehicle (p less than .01). Individual variation from human skin sources was evident (p less than .008). Chlordane accumulation in human plasma receptor fluid was the same for soil (0.04 +/- 0.05%) and acetone (0.07% +/- 0.06%) formulations. Most of the remaining chlordane was recovered in the soap and water skin surface wash. In contrast, in vivo percutaneous absorption of chlordane in the rhesus monkey was the same for soil (4.2 +/- 1.8%) and acetone (6.0 +/- 2.8%) formulations (p = .29, nonsignificant). Multiple soap and water washings were necessary to remove chlordane from skin, suggesting that a single wash may not adequately remove all the chlordane.

Acute toxicity, genotoxicity, and dermal carcinogenicity assessment of Isooctyl acrylate

Isooctyl acrylate (IOA) monomer is a complex mixture comprised predominantly of isomeric, eight-carbon alkyl esters of acrylic acid. Limited evidence from animal studies suggests that certain acrylate esters may be carcinogenic by the dermal route of exposure. The following studies were performed with IOA monomer: acute oral toxicity limit test in rats, primary dermal and ocular irritancy in rabbits, Ames Salmonella microsome assay, Saccharomyces cerevisiae D3 recombinogenicity assay, L5178Y TK +/- mouse lymphoma cell assay, and C3H/10T1/2 mouse embryo cell transformation assay. Finally, a limited dermal carcinogenicity bioassay was performed in which aliquots (25 microliters) of IOA monomer (5% v/v in acetone), IOA polymer (19% w/v in 70:30 acetone/heptane), or acetone (vehicle control) were applied to the shaved backs of male C3H/HeJ mice three times per week for the animals' lifetimes. IOA monomer had an acute oral LD50 in rats greater than 5000 mg/kg, was slightly irritating to the eyes and skin of rabbits on single exposures, and exhibited no genotoxic or cell-transforming potential. In the dermal carcinogenicity bioassay, no significant difference in mean survival times was observed between either treatment group and the control group. Animals treated with IOA monomer exhibited moderate dermatitis, surface crusting, hyperkeratosis, epidermal hyperplasia, diffuse melanosis, and one benign melanoma at the treatment size. Animals treated with IOA polymer exhibited varying degrees of dermatitis, surface crusting, and hyperkeratosis. Neither IOA monomer nor IOA polymer was carcinogenic under the conditions of the study.

Percutaneous absorption of [formula omitted] from soil

The objective was to determine percutaneous absorption of DDT and benzo[ a]pyrene in vitro and in vivo from soil into and through skin. Soil (Yolo County 65-California-57-8; 26% sand, 26% clay, 48% silt) was passed through 10-, 20-, and 48-mesh sieves. Soil then retained by 80-mesh was mixed with [ 14 C]-labeled chemical at 10 ppm. Acetone solutions at 10 ppm were prepared for comparative analysis. Human cadaver skin was dermatomed to 500 μm and used in glass diffusion cells with human plasma as the receptor fluid (3 ml/hr flow rate) for a 24-hr skin application time. With acetone vehicle, DDT (18.1 ± 13.4%) readily penetrated into human skin. Significantly less DDT (1.0 ± 0.7%) penetrated into human skin from soil. DDT would not partition from human skin into human plasma in the receptor phase (<0.1%). With acetone vehicle, benzo[ a]pyrene (23.7 ± 9.7%) readily penetrated into human skin. Significantly less benzo[ a]pyrene (1.4 ± 0.9%) penetrated into human skin from soil. Benzo[ a]pyrene would not partition from human skin into human plasma in the receptor phase (<0.1%). Substantivity (skin retention) was investigated by applying 14 C-labeled chemical to human skin in vitro for only 25 min. After soap and water wash, 16.7 ± 13.2% of DDT applied in acetone remained absorbed to skin. With soil only 0.25 ± 0.11% of DDT remained absorbed to skin. After soap and water wash 5.1 ± 2.1% of benzo[ a]pyrene applied in acetone remained absorbed to skin. With soil only 0.14 ± 0.13% of benzo[ a]pyrene remained absorbed to skin. In vivo percutaneous absorption of DDT in rhesus monkey was significantly less ( p < 0.02) from soil (3.3 ± 0.5%) than from acetone solution (18.9 ± 9.4%). DDT in vitro skin penetration values into human skin were similar to in vivo absorption values in the rhesus monkey. In vivo absorption in the rhesus was not statistically different from published in vivo absorption in man (10.4 ± 3.6%). In vivo percutaneous absorption of benzo[ a]pyrene in rhesus monkey was significantly less ( p < 0.015) from soil (13.2 ± 3.4%) than from acetone solution (51.0 ± 13.2%). Thus, with in vitro and animal in vivo systems relevant to man, skin absorption of DDT and benzo[ a]pyrene from soil was significantly less than when the chemicals were applied to skin in acetone solvent.

Percutaneous Absorption of [14C]DDT and [14C]Benzo[a]pyrene from Soil

The objective was to determine percutaneous absorption of DDT and benzo[a]pyrene in vitro and in vivo from soil into and through skin. Soil (Yolo County 65-California-57-8; 26% sand, 26% clay, 48% silt) was passed through 10-, 20-, and 48-mesh sieves. Soil then retained by 80-mesh was mixed with [14C]-labeled chemical at 10 ppm. Acetone solutions at 10 ppm were prepared for comparative analysis. Human cadaver skin was dermatomed to 500 microns and used in glass diffusion cells with human plasma as the receptor fluid (3 ml/hr flow rate) for a 24-hr skin application time. With acetone vehicle, DDT (18.1 +/- 13.4%) readily penetrated into human skin. Significantly less DDT (1.0 +/- 0.7%) penetrated into human skin from soil. DDT would not partition from human skin into human plasma in the receptor phase (less than 0.1%). With acetone vehicle, benzo[a]pyrene (23.7 +/- 9.7%) readily penetrated into human skin. Significantly less benzo[a]pyrene (1.4 +/- 0.9%) penetrated into human skin from soil. Benzo[a]pyrene would not partition from human skin into human plasma in the receptor phase (less than 0.1%). Substantivity (skin retention) was investigated by applying 14C-labeled chemical to human skin in vitro for only 25 min. After soap and water wash, 16.7 +/- 13.2% of DDT applied in acetone remained absorbed to skin. With soil only 0.25 +/- 0.11% of DDT remained absorbed to skin. After soap and water wash 5.1 +/- 2.1% of benzo[a]pyrene applied in acetone remained absorbed to skin. With soil only 0.14 +/- 0.13% of benzo[a]pyrene remained absorbed to skin.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of Topically Applied Radiolabeled Retinoids in Hairless Mouse Epidermis and Dermis After Single Applications

The retention of tritium-labeled all-trans-retinoic acid (RA), 13-cis-retinoic acid (13-cis-RA), aromatic retinoid, and arotinoid ethyl ester in the epidermis and dermis of hairless mice was measured up to 24 h following a single topical application in an acetone vehicle. The radioactivity in the tissues was extractable with chloroform:methanol, and the identities of the radioactive species extracted were confirmed as retinoids using thin-layer chromatography. All the retinoids were absorbed into the skin rapidly. After an initial period of distribution and penetration (lasting for about 1 h) the amount of the applied retinoid remaining in the epidermis and dermis decreased more slowly, obeying first order (exponential) decay kinetics. Both the arotinoid and the aromatic retinoid persisted for longer in the epidermis than equivalent doses of RA or 13-cis-RA. The half-lives of the retinoids in the dermis tended to be longer than in the epidermis, except for the arotinoid. Aromatic retinoid persisted for longest in the dermis with a half-life of 11 h.

Percutaneous Absorption of Nitroaromatic Compounds: In Vivo and In Vitro Studies in the Human and Monkey

The percutaneous absorption of 2-nitro-p-phenylene-diamine, 4-amino-2-nitrophenol, nitrobenzene, p-nitroaniline, and 2,4-dinitrochlorobenzene was measured through human and monkey skin. Human studies were performed with excised skin in diffusion cells. Absorption through monkey skin was measured by in vivo and in vitro techniques. Results were compared with those from previously reported human in vivo studies on 2,4-dinitrochlorobenzene and nitrobenzene. Rapid penetration was observed with all compounds, with maximum absorption occurring the first few hours. No significant differences in absorption were found in values obtained by the different procedures except for the highly volatile (and therefore difficult to compare) compound nitrobenzene. A comparison of the human and monkey in vitro data showed a trend toward increased absorption through monkey skin, but the increase was not statistically significant. The monkey in vivo and in vitro results showed that absorption of all compounds except nitrobenzene was slightly less in the in vitro studies; however, the values were not significantly different. The relative volatility of these nitroaromatic compounds was measured by the loss of compound from epidermal discs at various time intervals. The greatest loss of applied material occurred with nitrobenzene; however, substantial amounts of the other compounds were lost, particularly during the first minute after application as the acetone vehicle evaporated. Monkey skin was found to be a good model for human skin for the determination of the percutaneous absorption of these compounds, and in vitro measurements of absorption agreed reasonably well with values obtained by in vivo techniques. A good correlation was not observed between the absorption of these compounds and their solubility properties.