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Biomedical subjects

J E Riviere

Publications and source records attributed to J E Riviere.

At least 19 recordsLinked to original sources
PubMed2005

Comparative studies on the effects of water, ethanol and water/ethanol mixtures on chemical partitioning into porcine stratum corneum and silastic membrane.

The effects of water and ethanol vehicles on stratum corneum and silastic membrane partitioning of 11 industrial and agricultural compounds were studied to aid in characterizing and assessing risk from skin exposure. Zero percent, 50% and 100% aqueous ethanol solutions were used as solvents for (14)C labeled phenol, 4-nitrophenol, pentachlorophenol, dimethyl parathion, parathion, chloropyrifos, fenthion, triazine, atrazine, simazine and propazine. Compound partitioning between the solvents and porcine stratum corneum/silastic membrane were estimated. Stratum corneum was exposed to aqueous ethanol ranging from 0% to 100% v/v ethanol in 20% increments and Fourier transform infrared spectroscopy (FT-IR) was used to obtain an index of lipid disorder. Gravimetry and FT-IR were used to demonstrate lipid extraction in aqueous ethanol solutions. Partitioning patterns in silastic membranes resembled those in stratum corneum and were correlated with octanol/water partitioning. Partitioning was highest in water and was higher from 50% ethanol than from 100% ethanol, except for parathion, 4-nitrophenol, atrazine and propazine. Correlation existed between molecular weight and partitioning in water, but not in ethanol and ethanol/water mixtures. Lipid order, as reflected in FT-IR spectra, was not altered. These studies suggest that stratum corneum partitioning of the compounds tested is primarily determined by relative compound solubility between the stratum corneum lipids and the donor solvent. Linear relationships existed between octanol/water partitioning and stratum corneum partitioning. Partitioning was also correlated with molecular weight in water solvent systems, but not in ethanol and ethanol/water mixtures. Ethanol and ethanol/water mixtures altered the stratum corneum through lipid extraction, rather than through disruption of lipid order.

Animals↗
PubMed2004

Mixture additives inhibit the dermal permeation of the fatty acid, ricinoleic acid.

Ricinoleic acid (RA) like many of the ingredients in machine cutting fluids and other industrial formulations are potential dermal irritants, yet very little is known about its permeability in skin. 3H-ricinoleic acid mixtures were formulated with three commonly used cutting fluid additives; namely, triazine (TRI), linear alkylbenzene sulfonate (LAS), and triethanolamine (TEA) and topically applied to inert silastic membranes and porcine skin in vitro as aqueous mineral oil (MO) or polyethylene glycol (PEG) mixtures. These additives significantly decreased ricinoleic acid partitioning from the formulation into the stratum corneum (SC) in PEG-based mixtures. Except for LAS, all other additives produced a more basic formulation (pH = 9.3-10.3). In silastic membranes and porcine skin, individual additives or combination of additives significantly reduced ricinoleic permeability. This trend in ricinoleic acid disposition in both membranes suggests that the mixture interaction is more physicochemical in nature and probably not related to the chemical-induced changes in the biological membrane as may be assumed with topical exposures to potentially irritant formulations.

Alkanesulfonic Acids↗
PubMed2004

Meta-analysis of pharmacokinetic data of veterinary drugs using the Food Animal Residue Avoidance Databank: oxytetracycline and procaine penicillin G.

Investigators frequently face the quandary of how to interpret the often times disparate pharmacokinetic parameter values reported in the literature. Combining of data from multiple studies (meta-analysis) is a useful tool in pharmacokinetics. Few studies have explored the use of meta-analysis for veterinary species. Even fewer studies have explored the potential strengths and weaknesses of the various methods of performing a meta-analysis. Therefore, in this study we performed a meta-analysis for oxytetracycline (OTC) and procaine penicillin G (PPG) given intramuscularly to cattle. The analysis included 28 individual data sets from 18 published papers for PPG (288 data points), and 41 individual data sets from 25 published papers for OTC (489 data points). Three methods were used to calculate the parameters. The first was a simple statistical analysis of the parameter values reported in each paper. The second method was a standard Two-Stage Method (TSM) using the mean concentration vs. time data extracted from each paper. The third method was the use of nonlinear mixed effect modeling (NMEM) of the concentration vs. time data reported in the various papers, treating the mean data as if each set came from an individual animal. The results of this evaluation indicate that all three methods generate comparable mean parameter estimates for OTC and PPG. The only significant difference noted was for OTC absorption half-lives taken from the published literature, a difference attributable to the use of an alternative method of parameter calculation. The NMEM procedure offers the possibility of including covariates such as dose, age, and weight. In this study the covariates did not influence the derived parameters. A combination approach to meta-analysis of published mean data is recommended, where the TSM is the first step, followed by the NMEM approach.

Animals↗
PubMed2004

Feasibility of using half-life multipliers to estimate extended withdrawal intervals following the extralabel use of drugs in food-producing animals.

Under the Animal Medicinal Drug Use Clarification Act of 1994, veterinarians are legally allowed to use drugs in food-producing animals in an extralabel manner. This could potentially lead to violative residues in food of animal origin. It is therefore essential that an appropriately extended withdrawal interval be established. Ideally, these extended withdrawal intervals should be calculated on the basis of the tissue half-life of the drug in the target animal. However, these data are not readily available for all drugs of extralabel use in food-producing animals. For this reason, the use of a half-life multiplier has been proposed as a simple alternative method to estimate the effective tissue half-life of a drug. Extended withdrawal intervals, estimated using various half-life multipliers, were compared with the withdrawal intervals calculated using actual tissue half-lives. For the group of drugs investigated, a half-life multiplier of 5 resulted in estimates of extended withdrawal intervals that were potentially inadequate to prevent violative tissue residues for drugs that had relatively long tissue half-lives, high tolerances, or both. This is possibly because fewer half-lives are required for these drugs to reach the target tissue concentrations following administration at label doses. Use of a smaller half-life multiplier (in this case 3) is therefore suggested to ensure that extended withdrawal intervals are adequate to prevent violative tissue residues.

Algorithms↗
PubMed2003

The cytotoxicity of jet fuel aromatic hydrocarbons and dose-related interleukin-8 release from human epidermal keratinocytes.

Many jet fuel aromatic hydrocarbons are known carcinogens with the ability to both readily penetrate the skin with high absorptive flux and cause skin irritation. In order to evaluate the in vitro cutaneous toxicity of individual aromatic hydrocarbons in jet fuels and their potential for inducing skin irritation, we evaluated the LD(50), the highest non-cytotoxic (5% mortality) dose (HNTD), and interleukin-8 (IL-8) release activity of nine major jet fuel aromatic hydrocarbons in human epidermal keratinocytes (HEK). LD(50) ranged from 1.8 mM (0.03%) for cyclohexylbenzene to 82.9 mM (0.74%) for benzene, with a rank order potency of cyclohexylbenzene >trimethylbenzene >/=xylene >dimethylnaphthalene >ethylbenzene >toluene >benzene. The HNTD values ranged from 0.1 mM (0.001%) for cyclohexylbenzene to 48.2 mM (0.43%) for benzene. Naphthalene and methylnaphthalene could not be ranked in this comparison since their concentrations, presented as percentage saturation, were not comparable to the others presented as solutes in solution. There was a dose-related differential response in IL-8 release at 24 h. Toluene, xylene, trimethylbenzene, cyclohexylbenzene and dimethylnaphthalene significantly decreased IL-8 release at the respective HNTDs, while IL-8 release did not continue to decrease, or significantly increased (cyclohexylbenzene and dimethylnaphthalene), at the LD(50). IL-8 significantly increased with both doses of methylnaphthalene and naphthalene. The presence of hexadecane and mineral oil greatly attenuated the cytotoxicity elicited by individual aromatic hydrocarbons in HEK cells.

Aircraft↗
PubMed2002

Systemic uptake and cutaneous disposition of pentachlorophenol in a sequential exposure scenario: effects of skin preexposure to benzo[a]pyrene.

Characterizing interactions caused by sequential skin exposures to various environmental toxicants can be critical for a meaningful risk assessment. To assess sequential chemical exposure effect on chemical cutaneous disposition and systemic uptake of a toxicant, [(14)C]pentachlorophenol (PCP) was topically administered in three porcine skin models (in vivo, ex vivo, and in vitro) at 40 micro g/cm(2) with or without skin preexposure to benzo[a]pyrene (BaP), a known human carcinogen and cutaneous cytochrome P-450 (CYP450) inducer. In the mass balance studies, BaP skin preexposure was found to enhance (14)C absorption in all three models with detectable in vivo effect during the first several days. Total 8-h absorption was tripled by skin preexposure to BaP in the ex vivo (1.1 to 3.2%) and in vitro (0.20 to 0.66%) systems. As seen in the extended in vivo studies, total absorption was 50-57% regardless of exposure conditions, suggesting the prolonged observation period may conceal existing impact of potentially modified disposition processes, such as cutaneous metabolism, on systemic absorption. Skin preexposure to the skin CYP450 inducer BaP largely changed label penetration depth and distribution pattern in cutaneous tissues and decreased (14)C concentration in skin and fat. Additionally, BaP preexposure altered (14)C systemic tissue disposition, suggesting that altered cutaneous PCP disposition may eventually change the toxicity profile (cutaneous vs. systemic risk). The preliminary tissue distribution and systemic absorption data suggested that skin preexposure to BaP may considerably modify cutaneous biotransformation rate and thus deserves further investigation. The dermal model-dependent impacts of expected skin biotransformation manipulation by preexposure to chemicals such as BaP on cutaneous disposition and systemic uptake of environmental toxicants such as PCP need to be considered in risk assessment.

Adipose Tissue↗
PubMed2001

Enhanced systemic tissue distribution after dermal versus intravenous 3,3',4,4'-tetrachlorobiphenyl exposure: limited utility of radiolabel blood area under the curve and excretion data in dermal absorption calculations and tissue exposure assessment.

As a dioxin-like polychlorinated biphenyl (PCB), 3,3',4,4'-tetrachlorobiphenyl (TCB) is receiving increasing research and regulatory interest due to its high toxicity and persistence in the environment. (14)C-TCB was administered at an identical dose of 300 microg via the intravenous (iv) or dermal route to swine to examine the exposure route dependency of the relationship between tissue exposure and blood area under the curve (AUC) and the relationship between dermal absorption and excretion of radiolabel. After iv and dermal exposure, blood, urine, and feces samples were collected during the 11-day in vivo studies. At the end of the experiments, full mass balance studies were conducted to characterize tissue distribution of label. On average, over 70% of the applied dermal and iv doses were recovered. As expected, more than a 10-fold increase in blood AUC (0.49 vs 0.031, h x % dose/ml), plasma AUC (0.40 vs 0.038, h x % dose/ml), urine excretion (29 vs 2.3% of the applied dose), and fecal (30 vs 3.0% of the applied dose) excretion was determined after iv exposure compared to dermal exposure. However, we unexpectedly found that the tissue residue following iv exposure (8.0% of the applied dose) was only half that following dermal exposure (16% of the applied dose). Significantly larger (20- to 30-fold) ratios of blood AUC:tissue residue and excretion:tissue residue were observed after iv exposure compared to dermal exposure. This may indicate a route-related concentration-dependent blood-to-tissue partition process of pooled label, unique skin metabolism, or saturable hepatic metabolism of TCB. Thus, a long-term, low-input exposure pattern similar to this dermal exposure could be more harmful to systemic tissues than a short-term, high-dose exposure similar to this iv exposure. One should be aware that greater absorption, higher blood concentrations, greater blood and plasma AUCs, and greater excretion of label do not necessarily result in a greater overall tissue exposure and that some conventional approaches using label determination in blood and excreta without full mass balance studies may underestimate dermal absorption of chemicals similar to TCB.

Administration, Cutaneous↗
PubMed2001

Mixture effects of JP-8 additives on the dermal disposition of jet fuel components.

Aliphatic and aromatic components in formulated jet fuels can cause occupational dermatitis. However, the influence of JP-8 performance additives (DIEGME, 8Q21, and Stadis450) on the dermal disposition of fuel components is not well understood. These additives are formulated with commercial Jet-A to form military JP-8 fuel. The purpose of this study is to assess the influence of these additives on the dermal disposition of marker aromatic and aliphatic components, naphthalene and dodecane, respectively. Porcine skin sections in an in vitro system were used to characterize chemical-biological interactions that modulate diffusion of jet fuel components and isolated perfused porcine skin flaps (IPPSFs) were used to evaluate diffusion in a viable skin model with an intact microvasculature. In these 5-h studies, Jet-A, Jet-A + DIEGME, Jet-A + 8Q21, and Jet-A + Stadis450, Jet-A + DIEGME + 8Q21, Jet-A + DIEGME + Stadis450, Jet-A + 8Q21 + Stadis450, and JP-8 mixtures were tested. In general, naphthalene absorption (0.76-2.39% dose) was greater than dodecane absorption (0.10-0.84% dose), while the IPPSFs alone demonstrated that dodecane absorption was significantly greater in JP-8 than in Jet-A. Synergistic interactions with 8Q21 + Stadis450 appear to enhance systemic absorption of either naphthalene or dodecane, while DIEGME + Stadis450 increased naphthalene (1.88% dose) and dodecane (2.02% dose) penetration into the skin and fat tissues of IPPSFs. These findings were supported by the fact that 8Q21 + Stadis450 significantly increased dodecane flux and permeability in porcine skin sections, but 8Q21 alone reduced marker diffusion in both membrane systems. Furthermore, dodecane is more likely than naphthalene to remain in the stratum corneum and skin surface at 5 h, and DIEGME mixtures played a significant role in skin and surface retention of both markers. In summary, the data suggest that various combinations of these three performance additives in JP-8 can potentially alter the dermal disposition of aromatic and aliphatic fuel components in skin. More importantly, products of two-factor interactions were not predictable from single-factor exposures and, by extension, cannot be extrapolated to three-factor interactions.

Alkanes↗
PubMed2001

Potential and problems of developing transdermal patches for veterinary applications.

A new frontier in the administration of therapeutic drugs to veterinary species is transdermal drug delivery. The primary challenge in developing these systems is rooted in the wide differences in skin structure and function seen in species ranging from cats to cows. The efficacy of a transdermal system is primarily dependent upon the barrier properties of the targeted species skin, as well as the ratio of the area of the transdermal patch to the species total body mass needed to achieve effective systemic drug concentrations. A drug must have sufficient lipid solubility to traverse the epidermal barrier to be considered for delivery for this route. A number of insecticides have been developed in liquid "pour-on" formulations that illustrate the efficacy of this route of administration for veterinary species. The human transdermal fentanyl patch has been successfully used in cats and dogs for post-operative analgesia. The future development of transdermal drug delivery systems for veterinary species will be drug and species specific. With efficient experimental designs and available transdermal patch technology, there are no obvious hurdles to the development of effective systems in many veterinary species.

Administration, Cutaneous↗
PubMed2001

Cytokine induction as a measure of cutaneous toxicity in primary and immortalized porcine keratinocytes exposed to jet fuels, and their relationship to normal human epidermal keratinocytes.

The purpose of this study was to identify biomarkers of toxicity in primary porcine keratinocytes (PKC) and an immortalized porcine keratinocyte cell line (MSK3877) exposed to jet fuels Jet A, JP-8, and JP-8+100. Cells were exposed to 0.1% jet fuels and assayed for interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) mRNA using the TaqMan real time quantitative reverse transcriptase PCR assay. IL-8 and TNF-alpha protein release was measured using an ELISA. PKC exposed to jet fuels caused a slight upregulation of TNF-alpha mRNA at early time points, but no significant differences in TNF-alpha protein production were detected. IL-8 mRNA was increased at 4 h following exposure, and IL-8 protein was increased at 8 h. In MSK 3877 cells, jet fuels were shown to increase the production and expression of TNF-alpha mRNA and protein at 30 min and 1 h following exposure, respectively. IL-8 mRNA was only slightly induced compared to control. IL-8 protein release was suppressed by jet fuel exposure. These results were compared with those of a previous study in our laboratory to evaluate the utility of using porcine cells in lieu of normal human epidermal keratinocytes (NHEK). Similarities exist between PKC and NHEK with respect to both TNF-alpha and IL-8 production. The expression profile of TNF-alpha in MSK3877 cells mimics that of NHEK. In contrast, the profile of IL-8 expression opposes that of PKC and NHEK. These results suggest that porcine keratinocytes are susceptible to jet fuel toxicity. However, the responses of immortalized cells may vary from those of PKC and NHEK necessitating cautious interpretation of such data.

Analysis of Variance↗
PubMed2001

Mixture component effects on the in vitro dermal absorption of pentachlorophenol.

Interactions between chemicals in a mixture and interactions of mixture components with the skin can significantly alter the rate and extent of percutaneous absorption, as well as the cutaneous disposition of a topically applied chemical. The predictive ability of dermal absorption models, and consequently the dermal risk assessment process, would be greatly improved by the elucidation and characterization of these interactions. Pentachlorophenol (PCP), a compound known to penetrate the skin readily, was used as a marker compound to examine mixture component effects using in vitro porcine skin models. PCP was administered in ethanol or in a 40% ethanol/60% water mixture or a 40% ethanol/60% water mixture containing either the rubefacient methyl nicotinate (MNA) or the surfactant sodium lauryl sulfate (SLS), or both MNA and SLS. Experiments were also conducted with 14C-labelled 3,3',4,4'-tetrachlorobiphenyl (TCB) and 3,3',4,4',5-pentachlorobiphenyl (PCB). Maximal PCP absorption was 14.12% of the applied dose from the mixture containing SLS, MNA, ethanol and water. However, when PCP was administered in ethanol only, absorption was only 1.12% of the applied dose. There were also qualitative differences among the absorption profiles for the different PCP mixtures. In contrast with the PCP results, absorption of TCB or PCB was negligible in perfused porcine skin, with only 0.14% of the applied TCB dose and 0.05% of the applied PCB dose being maximally absorbed. The low absorption levels for the PCB congeners precluded the identification of mixture component effects. These results suggest that dermal absorption estimates from a single chemical exposure may not reflect absorption seen after exposure as a chemical mixture and that absorption of both TCB and PCB are minimal in this model system.

Administration, Topical↗
PubMed2001

Analysis of interleukin-8 release from normal human epidermal keratinocytes exposed to aliphatic hydrocarbons: delivery of hydrocarbons to cell cultures via complexation with alpha-cyclodextrin.

While inhalation exposures represent the predominant route for jet fuel toxicity, increased concern has been placed on topical exposures due to reports of severe contact dermatitis among military personnel. All three of the predominant aviation fuels currently used by the commercial and military sectors have been demonstrated experimentally to induce the production of interleukin-8 (IL-8), a proinflammatory cytokine, in normal human epidermal keratinocytes (NHEK). The objective of this study was to examine the effects of individual hydrocarbon components found in these fuels on IL-8 production by NHEK. In order to circumvent the extreme hydrophobicity of these compounds, inclusion complexes were formed between alpha-cyclodextrin/aliphatic hydrocarbons by adding 2 mM hydrocarbons to 4 mM alpha-cyclodextrin. NHEK were exposed to four aliphatic hydrocarbons (undecane, dodecane, tridecane, hexadecane) for 24 h at concentrations of 7.8-500 microM. These hydrocarbons caused a peak in IL-8 release at a concentration of 31.2 microM, with the exception of dodecane which peaked at 62.5 microM. Subtoxic concentrations of the aliphatic hydrocarbons were those < 62.5 microM. These studies demonstrate that the etiology of proinflammatory cytokine expression due to jet fuel exposure may be due in large part to the aliphatic hydrocarbon components. Furthermore, these studies provide additional evidence that hydrocarbons can be successfully delivered to cells in culture by encapsulating them in cyclodextrin inclusion complexes.

Cells, Cultured↗
PubMed2001

Effect of selective lipid extraction from different body regions on epidermal barrier function.

PURPOSE: To assess the effects of selective lipid extraction and tape stripping on transepidermal water loss (TEWL) at three body regions in the pig. METHODS: Lipids were extracted from the abdominal, inguinal. and back regions using three different solvent extraction procedures or cellophane tape stripping (15x) on Yorkshire pigs. Three solvent extraction stages were I, cyclohexane (5 ml for three, 1-min extractions): II, cyclohexane/ethanol (4:1) (5 ml for three, 1-min extractions): and III, cyclohexane/ethanol (1:4) (5 ml for three, 3-min extractions) extracted as follows: Site A, Stage I: Site B, Stage I and II; Site C, Stage I, II and III. Erythema, edema, and TEWL were assessed in control, tape-stripped, and extracted sites at 0, 6, and 24 h. The extracted lipids were analyzed by thin layer chromatography and quantified by densitometry for ceramide, cholesterol, cholesterol esters, fatty acids, and triglycerides. RESULTS: The change in TEWL (delta TEWL) in 14 of the 15 sites was the highest at 24 h and generally increased with each additional extraction. The greatest changes were present in the back. Each extraction stage removed specific lipids in reproducible quantities that caused the delta TEWL to increase from 0 to 24 h. Lipid removal was verified by transmission electron microscopy. The mean total lipid concentration depended on extraction solvents and body region, and was reproducible across sites and regions at equivalent stages of lipid extraction. Relative proportions of individual lipids extracted were similar across all body regions. Higher concentrations of total lipids were extracted from the back. CONCLUSIONS. These studies demonstrate that extraction of lipids increased the delta TEWL to a level similar to repeated tape stripping at all body sites in the pig. This study suggested that strategies that could biochemically alter epidermal lipid composition may increase absorption of simultaneously administered topical compounds and may be useful to enhance drug delivery.

Abdomen↗
PubMed2001

Mixed effects modeling of the disposition of gentamicin across domestic animal species.

An interspecies pharmacokinetic model for gentamicin was developed using the mixed effects modeling approach and serum disposition data obtained from the Food Animal Residue Avoidance Databank (FARAD). Data that met a priori quality criteria was obtained from the database and analysed using the traditional double logarithmic analysis and the mixed effects modeling approach. Body weight, brain weight and fever were the covariates of interest in our study. Population pharmacokinetic models across species were developed and validated with swine data. The parameter volume of distribution was modeled as a function of body weight. The total clearance was initially modeled as a function of body weight. The predictability performance of the model improved dramatically when the parameter brain weight was included in the covariate model for clearance. This was a surprising finding worthy of further study. The covariate fever seemed to influence the magnitude of the volume of distribution, although the scarcity of data pertaining to diseased animals makes this finding uncertain. We conclude that the pharmacokinetic characteristics of drugs such as gentamicin, can be predicted across species using a population pharmacokinetics modeling approach, and that clinical features that affect species in a similar manner can be also explored in this fashion.

Animals↗
PubMed2000

Identification of early biomarkers of inflammation produced by keratinocytes exposed to jet fuels jet A, JP-8, and JP-8(100).

The purpose of this study was to identify biomarkers of inflammation in normal human epidermal keratinocytes (NHEK) exposed to three jet fuel mixtures, Jet A, JP8, and JP8(100). NHEK were treated over 24 hours with 0.1% jet fuels, and mRNA production and protein release of two proinflammatory cytokines, IL-8 and TNF-alpha, were determined. Using an enzyme-linked immunosorbent assay (ELISA), NHEK were found to release both TNF-alpha and IL-8 in response to exposure to all three jet fuels. IL-8 release was noted within 8 hours and continued to rise through 24 hours compared to controls. Maximal levels of TNF-alpha release were seen at 4 hours and decreased in a time-dependent manner, although these levels remained above control levels at all time points assayed. mRNA for IL-8 was elevated 4 hours following exposure to the fuels, which was detected via a quantitative competitive reverse transcriptase-polymerase chain reaction (RT-PCR). mRNA for TNF-alpha was detected at all time points assayed but was not quantified. These results demonstrate that jet fuels induce the production and release of proinflammatory cytokines in NHEK and thus create the potential for chronic inflammation, which may contribute to the development or progression of disease states in the skin.

Biomarkers↗
PubMed2000

Dermatoxicokinetic modeling of p-nitrophenol and its conjugation metabolite in swine following topical and intravenous administration.

The development of a dermatotoxicokinetic (dTK) model for p-nitrophenol (PNP), a common metabolite from a variety of compounds and a biomarker of organophosphate (OP) insecticide exposure, may facilitate the kinetic modeling and risk assessment strategy for its parent compounds. In order to quantify and then clarify in vivo-in vitro correlation of PNP disposition, multicompartment kinetic models were formulated. Female weanling pigs were dosed with [14C]PNP intravenously (150 microg in ethanol, n = 4) or topically onto non-occluded abdominal skin (300 microg/7.5cm2 in ethanol, n = 4). PNP and p-nitrophenyl-beta-D-glucuronide (PNP-G) profiles were determined in plasma and urine in addition to total 14C quantitation in many other samples. Disposition parameters (rate constants, Ftop, T12, T1/2Ka, AUC, Vss, Clp, MAT, and MRT) and the simulated chemical mass-time profiles on the dosed skin surface and in the local, systemic, and excretory compartments were also determined. Total recoveries of 97.17 +/- 4.18% and 99.80 +/- 2.41% were obtained from topical and intravenous experiments, respectively. Ninety-six hours after topical and intravenous application, 70.92 +/- 9.72% and 98.65 +/- 2.43% of the dose were excreted via urine, and 0.55 +/- 0.16% and 0.51 +/- 0.10% via the fecal route, respectively. Peak excretion rate and time were also determined. It was suggested by experimental observation and modeling that urinary 14C excretion correlates with the systemic tissue depletion profile well and may be used as a biomarker of PNP exposure. This study also supports the strategy of using urinary PNP as a biomonitoring tool for OP pesticide exposure, although some precautions have to be taken. The strategy used in this study will be useful in comprehensive dTK modeling in dermal risk assessment and transdermal drug delivery.

Administration, Topical↗
PubMed2000

Comparative in vitro percutaneous absorption of nonylphenol and nonylphenol ethoxylates (NPE-4 and NPE-9) through human, porcine and rat skin.

The purpose of this study was to assess the percutaneous absorption of nonylphenol (NP) and the nonylphenol ethoxylates, NPE-4 and NPE-9, in human, porcine and rat skin. In vitro studies with the NPEs were conducted for 8 h in flowthrough diffusion cells using topical solutions of 0.1, 1.0 and 10% in PEG-400 or 1% in water (NPE-9 only). NP absorption was assessed as a 1% solution in PEG-400. All compounds were 14C ring-labeled and radioactivity in perfusate was monitored over time. Skin deposition was measured at the termination of the experiment. Absorption into perfusate and total penetration (compound absorbed plus compound sequestered in skin) were calculated. Absorption of NPE-4, NPE-9 and NP was similar across all species at less than 1% of the applied dose over 8 h. Penetration was generally below 5% of applied dose, the majority located in the stratum corneum. In all species and for both NPEs, the fraction of dose absorbed was highest for the lowest applied dose. Absorptions expressed as actual mass absorbed over 8 h were similar (approximately 0.3 microg/cm2) across all concentrations. Penetration, but not absorption, was greater from a water vehicle compared to a PEG-400 vehicle, particularly in rat skin. These studies suggest that NP, NPE-4 and NPE-9 were minimally absorbed across skin from all three species. Fractional absorption was concentration-dependent, making the actual absorbed flux constant across all doses.

Animals↗