Pet collars containing tetrachlorvinphos (TCVP): evaluation of the results of torsion and on-animal release studies and implications for post-application consumer exposure and risk analysis.

Tetrachlorvinphos (TCVP) is the pesticidal active ingredient found in some flea and tick collars for dogs and cats. Recent studies sponsored by The Hartz Mountain Corporation, confirm the safety of TCVP as an active ingredient in pet collars. Based upon data from these new studies and results previously relied upon by the U.S. Environmental Protection Agency, the following conclusions have been made: Torsion study data clearly indicate that approximately 93% of released formulation from TCVP containing pet collars is in a liquid phase immediately following activation.Further, even more relevant to human health risk analysis associated with post-application exposures, in vivo data from dogs wearing TCVP pet collars definitively document that TCVP dust released from the collar is rapidly absorbed into the sebum. The maximum ratio of dust to liquid was 0.023% dust to 99.977% liquid.In vivo fur data provide scientific evidence confirming that the mechanism of dissemination of TCVP from pet collars is as a liquid suspended or dissolved in the animal's sebum, even though it may be released from the collar as a solid. Thus, potential post-application exposure to TCVP, including immediately following collar placement, is almost entirely to a liquid phase.Based upon EPA's refined and conservative "untrimmed" collar risk assessment, post-application incidental oral hand-to-mouth activity by children aged 1 to <2 years of age results in margins of exposure significantly greater than the level of concern of 1000, and therefore do not present unreasonable health risk.

Estimated Dermal Penetration of Tetrachlorvinphos (TCVP) in Humans Based on In Silico Modeling and In Vitro and In Vivo Data.

Tetrachlorvinphos (TCVP) is the pesticidal active ingredient in some collars for dogs and cats. The objective of this study was to provide a refined estimate of dermal penetration of TCVP in humans using in silico predictions as well as in vitro and in vivo data. The in vivo dermal absorption of TCVP was previously studied in the rat and shown to be saturable, ranging from 21.7% (10 µg/cm2) down to 3% (1000 µg/cm2) Subsequent in silico predictions were conducted for rats and humans to provide initial evaluations of species and dose-dependent differences in dermal absorption. A definitive comparison of TCVP systemic exposure in rat and human following dermal application was then conducted via a standard in vitro assay. TCVP dose levels of 10, 100, or 1000 µg/cm2 were applied to excised rat and human skin mounted in flow-through diffusion cells. The vehicle was 1% hydroxypropylmethylcellulose (HPMC) in water. An additional 5 µg/cm2 dose was applied to excised human skin only. The in vitro dermal absorption of TCVP was also assessed from artificial sebum at dose levels of 5, 10, or 100 µg/cm2 applied to human skin only. Utilizing the so-called triple pack approach with in vitro and in vivo rat data and in vitro human data, dermal absorption for TCVP was calculated for humans. In silico modeling indicated absorption of TCVP through human skin might be 3- to 4- fold lower than rat skin at all application levels, with a maximum dermal absorption of 9.6% at the lowest exposure of 10 µg/cm2, down to 0.1% at 1000 µg/cm2. Similar species differences were also found in the definitive in vitro absorption assays. Modeling overestimated TCVP human dermal absorption (9.6%) as compared to excised human skin results (1.7%) for the HPMC vehicle at the lowest exposure (10 µg/cm2), with better agreement at the higher exposures. Conversely, modeling accurately predicted rat dermal absorption (27.9%) as compared to in vivo rat results (21.7%) at the lowest exposure in HPMC, with diminished agreement at the higher exposures. As a first approximation, in silico estimates of dermal absorption are useful; however, these tend to be more variable than in vitro or in vivo measurements. TCVP dermal penetration measured in vitro was lower in 1% HPMC vehicle as compared to artificial sebum. For the 1% HPMC vehicle, in vitro rat dermal absorption was similar to data obtained for in vivo rats, giving confidence in the triple pack approach. In consideration of the triple pack approach, estimated human dermal absorption from 1% HPMC was ≤2%. Based upon excised human skin determinations directly, estimated human dermal absorption of TCVP from artificial sebum was ≤7%.

Best practices for exposure model peer review - A SciPinion advisory panel report.

The extent and rigor of peer review that a model undergoes during and after development influences the confidence of users and managers in model predictions. A process for determining the breadth and depth of peer review of exposure models was developed with input from a panel of exposure-modeling experts. This included consideration of the tiers and types of models (e.g., screening, deterministic, probabilistic, etc.). The experts recommended specific criteria be considered when evaluating the degree to which a model has been peer reviewed, including quality of documentation and the model peer review process (e.g., internal review with a regulatory agency by subject matter experts, expert review reports, formal Scientific Advisory Panels, and journal peer review). In addition, because the determination of the confidence level for an exposure model's predictions is related to the degree of evaluation the model has undergone, irrespective of peer review, the experts recommended the approach include judging the degree of model rigor using a set of specific criteria: (1) nature and quality of input data, (2) model verification, (3) model corroboration, and (4) model evaluation. Other key areas considered by the experts included recommendations for addressing model uncertainty and sensitivity, defining the model domain of applicability, and flags for when a model is used outside its domain of applicability. The findings of this expert engagement will help developers as well as users of exposure models have greater confidence in their application and yield greater transparency in the evaluation and peer review of exposure models.

Assessing Durability and Safety of Permethrin Impregnated Uniforms Used by Outdoor Workers to Prevent Tick Bites after One Year of Use.

Long lasting permethrin-impregnated (LLPI) clothing can retain permethrin and repel ticks for up to three months and without exceeding EPA-approved safe levels; however, little is known about longer term effects of wearing LLPI clothing. Here, permethrin content was measured in new forester pants soon after initial impregnation (Insect Shield) and again one year later after being repeatedly worn by foresters in the field. Urine samples were collected from foresters for biomonitoring of permethrin metabolites at multiple time intervals (pre-use, one-month, three-to-four-months, and one-year post-use). Lethality against nymphal Ixodes scapularis Say was measured in clothing after one year of wear by foresters. Furthermore, to test potential variability in permethrin impregnation of different batches of clothing, separate sets of clothing were anonymously sent to Insect Shield for permethrin treatment over a period of three months and permethrin was quantified. Results demonstrated 33% of participants' pants had no measurable permethrin after one year of wear and permethrin content and tick mortality varied significantly between clothing. Only two of the participants' clothing resulted in ≥ 30% tick mortality after one year of wear. Significant differences were observed in 3-PBA and trans-DCCA, but not cis-DCCA metabolites in participants over the four measured time points and were higher than general United States population levels. This study provides practical information on the safety (measured by urinary metabolites) over time of LLPI clothing. It also provides snapshots (pre-washing and after one year of wear) of effectiveness of LLPI clothing as personal protective equipment against ticks for outdoor workers.

Weight of evidence analysis of the tumorigenic potential of 1,3-dichloropropene supports a threshold-based risk assessment.

1,3-Dichloropropene (1,3-D; CAS #542-75-6) is a fumigant used for preplant treatment of soil to control parasitic nematodes and manage soil borne diseases for numerous fruit, vegetable, field and tree and vine crops across diverse global agricultural areas. In the USA, 1,3-D has historically been classified by the U.S. EPA as likely to be carcinogenic to humans via both oral and inhalation routes. This classification for the oral route was primarily based upon increases in multiple tumor types observed in National Toxicology Program (NTP) cancer bioassays in rats and mice, while the classification for the inhalation route was based upon increased benign bronchioloalveolar adenomas in a mouse study conducted by The Dow Chemical Company. Based on U.S. EPA standard risk assessment methodologies, a low-dose linear extrapolation approach has been used to estimate risks to humans. Furthermore, genotoxicity associated with 1,3-D was historically considered a potential mode of action (MOA) for its tumorigenicity. New information is available and additional studies have been conducted that reveal a different picture of the tumorigenic potential of 1,3-D. These data and information include: (1) initial cancer studies by the NTP were conducted on an antiquated form of 1,3-D which contained a known mutagen/carcinogen, epichlorohydrin, as a stabilizer while current 1,3-D fumigants use epoxidized soybean oil (ESO) as the stabilizer; (2) results from two additional oral rodent cancer bioassays conducted on the modern form of 1,3-D became available and these two studies reveal a lack of carcinogenicity; (3) a newly conducted Big Blue study in F344 rats via the oral route further confirms that 1,3-D is not an in vivo genotoxicant; and (4) a newly conducted repeat dose inhalation toxicokinetic (TK) study shows that linear dose proportionality is observed below 30 ppm, which demonstrates the non-relevance of 60 ppm 1,3-D-induced benign lung tumors in mice for human health assessment. This weight of evidence review is organized as follows: (a) the TK of 1,3-D are presented because of relevant considerations when evaluating test doses/concentrations and reported findings of tumorigenicity; (b) the genotoxicity profile of 1,3-D is presented, including a contemporary study in order to put a possible genotoxicity MOA into perspective; (c) the six available bioassays are reviewed followed by (d) scientifically supported points of departure (PODs) and evaluation of human exposure for use in risk assessment. Through this assessment, all available data support the conclusion that 1,3-D is not a tumorigen at doses below 12.5 mg/kg bw/day via the oral route or at doses below 30 ppm via the inhalation route. These findings and clearly identified PODs show that a linear low dose extrapolation approach is not appropriate and a threshold-based risk assessment for 1,3-D is human health protective. Finally, in 2019, the Cancer Assessment Review Committee (CARC) reevaluated the carcinogenic potential of 1,3-D. In accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment, the CARC classified 1,3-D (Telone) as "Suggestive Evidence of Carcinogenic Potential based on the presence of liver tumors by the oral route in male rats only." Given this finding, EPA stated that "quantification of human cancer risk is not required. The CARC recommends using a non-linear approach (i.e. reference dose (RfD)) that will adequately account for all chronic toxicity including carcinogenicity, that could result from exposure to 1,3-dichloropropene."

Bioabsorption and effectiveness of long-lasting permethrin-treated uniforms over three months among North Carolina outdoor workers.

BACKGROUND: Vector-borne diseases are an important cause of morbidity and mortality in the USA. Effective, convenient prevention methods are needed. Long-lasting permethrin-impregnated (LLPI) clothing can prevent tick bites, however, additional information is needed on the real-world effectiveness and safety of this preventative measure. METHODS: In this pilot study, we recruited state and county park employees from North Carolina to wear LLPI uniforms for three months during the summer of 2016. We collected spot urine samples for biomonitoring of permethrin metabolites at one week, one month and three months after first use of the LLPI uniform. Following three months of wear, we collected pants and socks and analyzed them for permethrin content and mortality to ticks and mosquitoes. RESULTS: Thirteen park employees were included in the analysis. Bioactive amounts of permethrin remained in all clothing swatches tested, although there was great variability. Tick mortality was high, with 78% of pant and 88% of sock swatches having mean knockdown percentages ≥ 85%. In contrast, mosquito mortality was low. Over the study period, the absorbed dosage of permethrin averaged < 4 µg/kg/d of body weight based on measurements of three metabolites. CONCLUSIONS: LLPI clothing retained permethrin and bioactivity against ticks after three months of use in real-world conditions. The estimated absorbed dosage of permethrin was well below the U.S. EPA level of concern, suggesting that LLPI clothing can be used safely by outdoor workers for tick bite prevention.

Modeling duration of time lived in a residence, a community and mobility in rural areas of Merced and Ventura, California to assess potential health risks to airborne contaminants.

A de novo population mobility survey of 800 households (random digit dialing-based phone interviews) was conducted in high demand areas of the agricultural fumigant, 1,3-dichloropropene (1,3-D) in Merced and Ventura counties of California. The survey included approximately 20 questions relating to the length of time individuals had lived in the high demand areas in each county, and also relating to weekly and annual mobility patterns. Lifetime inhalation exposures to 1,3-D are determined, in part, by the number of years individuals spend in an area where the fumigant is used. The purpose of the survey was to provide location-specific data for probabilistic modeling of long-term inhalation exposures to 1,3-D. The survey found that the majority of residents do not live in a high demand area or in the same house (99.99%) for 70years (a default assumption used by some regulatory agencies). It was also observed that residents move frequently and are mobile day-to-day and week-to-week, within the use area. Finally, estimates of total residency duration, derived from the survey results indicate that median times spent within a high demand area (which could include more than one residential location) were 18 and 26years for Ventura and Merced high demand areas, respectively. The average time spent in the high demand areas was 22 and 27years for the Ventura and Merced community, respectively. Less than 0.01% of the populations in either of the high demand areas spend 70years in the same house.

Evaluation of potential human health effects associated with the agricultural uses of 1,3-D: Spatial and temporal stochastic risk analysis.

Dow AgroSciences (DAS) markets and sells 1,3-Dichloropropene (1,3-D), the active ingredient in Telone®, which is used as a pre-plant soil fumigant nematicide in economically important crops in California. 1,3-D has been regulated as a "probable human carcinogen" and the California Department of Pesticide Regulation limits use of 1,3-D based on human health risk assessments for bystanders. This paper presents a risk characterization for bystanders based on advances in the assessment of both exposure and hazard. The revised bystander risk assessment incorporates significant advances: 1) new data on residency duration and mobility in communities where 1,3-D is in high demand; 2) new information on spatial and temporal concentrations of 1,3-D in air based on multi-year modeling using a validated model; and 3) a new stochastic spatial and temporal model of long-term exposures. Predicted distributions of long-term, chronic exposures indicate that current, and anticipated uses of 1,3-D would result in lifetime average daily doses lower than 0.002mg/kg/d, a dose associated with theoretical lifetime excess cancer risk of <10(-5) to >95% of the local population based on a non-threshold risk assessment approach. Additionally, examination of 1,3-D toxicity studies including new chronic toxicity data and mechanism of action supports the use of a non-linear, threshold based risk assessment approach. The estimated maximum annual average daily dose of <0.0016mg/kg/d derived from the updated exposure assessment was then compared with a threshold point of departure. The calculated margin of exposure is >1000-fold, a clear indication of acceptable risk for human health. In summary, the best available science supports 1,3-D's threshold nature of hazard and the revised exposure assessment supports that current agricultural uses of 1,3-D are associated with reasonable certainty of no harm, i.e., estimated long-term exposures pose insignificant health risks to bystanders even when the non-threshold approach is assumed.

Cyphenothrin Flea and Tick Squeeze-On for Dogs: Evaluation of Potential Health Risks Based on the Results of Observational Biological Monitoring.

An observational biomonitoring study was conducted involving adults and children in households that purchased and applied a cyphenothrin-containing spot-on product for dogs as part of their normal pet care practices. The 3- to 6-yr-old children had greater exposure than the adult applicators in the same house, 3.8 and 0.6 µg/kg body weight, respectively. The mean measured values in children were 13-fold lower than those estimated using the U.S. Environmental Protection Agency (EPA) current standard operating procedures (SOP) for pet products (assuming 5% dermal absorption), although the maximum absorbed dosage of one child on one day was equivalent to the default value derived from the SOPs. With regard to potential human health risks, it can be concluded that despite the inherent conservatism in both the exposure and toxicology data, the margins of exposure (MOE) were consistently greater than 100 for average, 95th percentile, and maximum exposures. More specifically, the results of this study demonstrated that the MOE were consistently greater than 1,000 for mean exposures and exceeded 100 for 95th percentile and maximum measured exposures, which clearly indicates a reasonable certainty of no harm when using the cyphenothrin spot-on products. It is also noteworthy that Sergeant's spot-on products containing cyphenothrin currently sold in the United States have lower weight percentages of active ingredient and lower applied amounts than those used by all but two of the participant households in this study.

Measurement of the temporal transferability of indoxacarb to cotton gloves from spot-on treated dogs.

The objectives of the studies reported herein were to (1) determine the minimum number of petting simulations required to load the maximum amount of test substance (indoxacarb) residue onto cotton gloves (the sampling medium) from spot-on treated dogs; and (2) using the number of petting simulations that resulted in maximal transfer, to conduct a second study that measured amount of residue dislodged via petting a dog as a function of the time interval after application. Maximal percent transfer of indoxacarb from spot-on treated dogs occurred after 10 repetitive petting simulations (consisting of 3 directional pet strokes each) and was approximately 1-2% of amount applied. Temporal measurements of mean indoxacarb transferability followed an exponential decay function, beginning at approximately 2% transfer on the day of application, and declining to 0.08% by d 30 post treatment.

Communication-and-resolution programs: the challenges and lessons learned from six early adopters.

In communication-and-resolution programs (CRPs), health systems and liability insurers encourage the disclosure of unanticipated care outcomes to affected patients and proactively seek resolutions, including offering an apology, an explanation, and, where appropriate, reimbursement or compensation. Anecdotal reports from the University of Michigan Health System and other early adopters of CRPs suggest that these programs can substantially reduce liability costs and improve patient safety. But little is known about how these early programs achieved success. We studied six CRPs to identify the major challenges in and lessons learned from implementing these initiatives. The CRP participants we interviewed identified several factors that contributed to their programs' success, including the presence of a strong institutional champion, investing in building and marketing the program to skeptical clinicians, and making it clear that the results of such transformative change will take time. Many of the early CRP adopters we interviewed expressed support for broader experimentation with these programs even in settings that differ from their own, such as systems that do not own and control their liability insurer, and in states without strong tort reforms.

Revised methods for estimating potential reentry exposure associated with indoor crack and crevice and perimeter application.

Surface deposition of insecticides applied as indoor residential foggers, baseboard or perimeter sprays, spot sprays, and crack-and-crevice (C&C) sprays represent pathways of unintentional, postapplication exposure for children and adults. Estimation of the magnitude of this exposure following an application event is associated with uncertainty due to many factors, including (1) surface residue deposition and distribution, (2) access to and the nature of contact with treated surfaces based on time-activity patterns of residents, and (3) the role of residue removal mechanisms such as cleaning treated surfaces, pesticide degradation or redistribution, and hand washing and bathing following contact. A comparative spatial deposition study was conducted involving broadcast, perimeter, and C&C application methods. Residues measured using a spatial grid of deposition dosimeters on floor surfaces demonstrated significantly lower residue concentrations in readily accessible areas following C&C and perimeter applications, versus broadcast treatment. Analyses of other monitoring studies support this finding. The implications of these findings are discussed for both screening-level and higher tier probabilistic postapplication, residential exposure assessment. The U.S. Environmental Protection Agency (EPA) current guidance on interpretation of deposition following C&C application is supported by data in this study and others that indicate a ratio of 10:1 for deposition for broadcast versus C&C application. However, the perimeter deposition data are quite similar to C&C deposition and do not support a 70/30 default relative to broadcast recommended by the U.S. EPA (2012).

2,4-D exposure and risk assessment: comparison of external dose and biomonitoring based approaches.

Conventional chemical exposure assessment relies upon measurements or estimates of chemical concentrations in environmental media, food, or products, in combination with assumptions regarding contact rates, in order to estimate external doses (ppm in air) or intake rates of chemicals (e.g., mg/kg/day ingested). A risk assessment is conducted by comparing these external or intake dose estimates to appropriate (e.g., route-specific) exposure guidance values (e.g., Reference Dose or Reference Concentration) to assess whether exposures are exceeding levels of concern. Human biomonitoring, in which concentrations of chemicals are measured in blood or urine, is being increasingly used as an alternative or complementary exposure assessment. The Biomonitoring Equivalent, which is the translation of a Reference Dose to an equivalent concentration of a compound in blood or urine, provides a parallel means to interpret biomonitoring data in order to assess whether chemical-specific exposures exceed levels of concern. This manuscript presents a side-by-side comparison of the two approaches for assessing exposures and risks for a case study compound, 2,4-dichlorophenoxyacetic acid (2,4-D). The findings from this case study indicate that the external dose-based assessments result in estimates of exposure and resulting hazard quotients that are consistently several-fold higher than those based on biomonitoring data. These comparisons support a conclusion that exposure assessments conducted as part of the registration process for 2,4-D incorporate sufficiently conservative assumptions.

Estimating human exposure: improving accuracy with chemical markers.

Exposure to chemicals, natural as well as anthropogenic, occurs in the human environment. In the absence of chemical-specific data for the wide variety of exposure scenarios, federal agencies have adopted two approaches to estimating exposures. The first is to set chemical standards for exposures, usually through a single route. These standards are set based on risk assessment principles and economic feasibility. When there are standards, measurement of environmental chemical concentrations can be used to prevent unacceptable levels of exposure. The second approach is to estimate external exposure (typically route-specific) and/or an absorbed dose using a series of assumptions regarding translation of chemical concentrations from one part of the environment to another, human activity patterns, and chemical absorption through various routes into the body. These assumptions have been converted into algorithms that can be used to estimate a human exposure and dosage, typically expressed on body weight basis. These algorithms, designed to avoid underestimations of human exposure, have, in some instances, been incorporated into computer models. Chemical markers, measured either as the parent compound or as metabolites in human populations with known exposure to the parent compound, can be applied to improve the accuracy of these estimates of exposure.

Comparison of four probabilistic models (CARES(®), Calendex™, ConsExpo, and SHEDS) to estimate aggregate residential exposures to pesticides.

Two deterministic models (US EPA's Office of Pesticide Programs Residential Standard Operating Procedures (OPP Residential SOPs) and Draft Protocol for Measuring Children's Non-Occupational Exposure to Pesticides by all Relevant Pathways (Draft Protocol)) and four probabilistic models (CARES(®), Calendex™, ConsExpo, and SHEDS) were used to estimate aggregate residential exposures to pesticides. The route-specific exposure estimates for young children (2-5 years) generated by each model were compared to evaluate data inputs, algorithms, and underlying assumptions. Three indoor exposure scenarios were considered: crack and crevice, fogger, and flying insect killer. Dermal exposure estimates from the OPP Residential SOPs and the Draft Protocol were 4.75 and 2.37 mg/kg/day (crack and crevice scenario) and 0.73 and 0.36 mg/kg/day (fogger), respectively. The dermal exposure estimates (99th percentile) for the crack and crevice scenario were 16.52, 12.82, 3.57, and 3.30 mg/kg/day for CARES, Calendex, SHEDS, and ConsExpo, respectively. Dermal exposure estimates for the fogger scenario from CARES and Calendex (1.50 and 1.47 mg/kg/day, respectively) were slightly higher than those from SHEDS and ConsExpo (0.74 and 0.55 mg/kg/day, respectively). The ConsExpo derived non-dietary ingestion estimates (99th percentile) under these two scenarios were higher than those from SHEDS, CARES, and Calendex. All models produced extremely low exposure estimates for the flying insect killer scenario. Using similar data inputs, the model estimates by route for these scenarios were consistent and comparable. Most of the models predicted exposures within a factor of 5 at the 50th and 99th percentiles. The differences identified are explained by activity assumptions, input distributions, and exposure algorithms.

Concurrent 2,4-D and triclopyr biomonitoring of backpack applicators, mixer/loader and field supervisor in forestry.

Two herbicides, 2,4-D and triclopyr esters (application ratio 1.6:1 acid equivalents) were applied as a tank mix by a crew of 8 backpack sprayer applicators, a mixer/loader, and a field supervisor. The crew was employed in a conifer release program in northern California during the summer of 2002. Biomonitoring (urine, 24 h) utilized 2,4-D and triclopyr (a.e.) as rapidly excreted exposure biomarkers. The absorbed dosages of 2,4-D and triclopyr were calculated based upon cotton whole body suits and biomonitoring. Dosages based upon accumulation of the herbicides on body suits averaged 42.6 µg (a.e.) 2,4-D/kg-d and 8.0 µg (a.e.) triclopyr/kg-d. Six consecutive days of concurrent urine collections showed that backpack applicators excreted an average of 11.0 µg (a.e.) 2,4-D/kg-d and 18.9 µg (a.e.) triclopyr/kg-d. Estimates based upon curve fitting were 17.1 and 29.3 µg (a.e.)/kg-d, respectively. Results suggest that passive dosimetry for 2,4-D consistently overestimated the dosage measured using biomonitoring by a factor of 2-3 fold, while for triclopyr, passive dosimetry underestimated the absorbed dose based on biomonitoring by a factor of 2-4 fold.

Value-driven ERM: making ERM an engine for simultaneous value creation and value protection.

Enterprise risk management (ERM) began as an effort to integrate the historically disparate silos of risk management in organizations. More recently, as recognition has grown of the need to cover the upside risks in value creation (financial and otherwise), organizations and practitioners have been searching for the means to do this. Existing tools such as heat maps and risk registers are not adequate for this task. Instead, a conceptually new value-driven framework is needed to realize the promise of enterprise-wide coverage of all risks, for both value protection and value creation. The methodology of decision analysis provides the means of capturing systemic, correlated, and value-creation risks on the same basis as value protection risks and has been integrated into the value-driven approach to ERM described in this article. Stanford Hospital and Clinics Risk Consulting and Strategic Decisions Group have been working to apply this value-driven ERM at Stanford University Medical Center.

Estimation of the percutaneous absorption of permethrin in humans using the parallelogram method.

The objective of this study was to develop an estimate of the percent dermal absorption of permethrin in humans to provide more accurate estimates of potential systemically absorbed dose associated with dermal exposure scenarios. Piperonyl butoxide (PBO) was used as a reference compound. The human percutaneous absorption estimate was based on the assumption that the ratio of in vivo dermal absorption (expressed as a percentage during a given time period) of permethrin through rat skin to in vitro dermal absorption through rat skin was the same as the ratio of in vivo dermal absorption in humans to in vitro dermal absorption with human skin, known as the parallelogram method. The ratio of dermal absorption by in vitro rat skin to absorption by in vitro human skin ranged from 6.7 to 15.4 (for a 24-h exposure period) with an average of 11. Data suggest in vivo human dermal absorption values for permethrin ranging from 1.4 to 3.3% when estimated based on 24-h in vivo rat values, and 2.5 to 5.7% based on 5-d in vivo rat values. The parallelogram method used to estimate dermal absorption of permethrin and PBO is supported by results from several other compounds for which in vivo and in vitro rat and human dermal absorption data exist. Collectively, these data indicate that estimating human dermal absorption from in vitro human and rat plus in vivo rat data are typically accurate within ±3-fold of the values measured in human subjects.

Experimental methods for determining permethrin dermal absorption.

The objectives of this study were to (1) determine the percutaneous absorption of radiolabeled permethrin and piperonyl butoxide (PBO) in vivo in rats and in vitro to permit a calculation of the ratio of in vitro to in vivo values, and (2) test a method of estimating in vivo human absorption. Carbon-14 labeled permethrin in ethanol solution was applied to the clipped skin of rats in vivo at doses of 2.25, 20, or 200 µg/cm2. As a reference compound, 14C-labeled PBO in isopropanol solution was applied to rat skin in vivo at a dose of 100 µg/cm2. All applications were washed at 24 h postapplication, and rats were sacrificed either at 24 h for permethrin or 5 d for both compounds. The radiolabel recovered from carcass, urine including cage wash, and feces was summed to determine percent absorption. For the 24-h time point, at doses of 2.25, 20, and 200 µg/cm2 of permethrin, values of 22, 22, and 28%, respectively, were obtained for in vivo rat percutaneous absorption (n=6 per dose). For the 5-d time point, at doses of 2.25, 20, and 200 µg/cm2 of permethrin, values of 38, 38, and 30%, respectively, were obtained for in vivo rat percutaneous absorption (n=6 per dose). The 5-d percutaneous absorption of 14C-PBO at 100 µg/cm2 was determined to be 42% (n=6). Dose and test duration did not exert a statistically significant effect on percutaneous absorption of permethrin in the rat in vivo. For in vitro absorption determination, 14C-permethrin in ethanol solution was applied to freshly excised human skin in an in vitro test system predictive of skin absorption in humans. Twenty-four hours after application, the radiolabel recovered from dermis and receptor fluid was summed to determine percent absorption. At doses of approximately 2.25, 20, and 200 µg/cm2 permethrin, values of 1, 3, and 2%, respectively, were obtained for percutaneous absorption (n=9 per dose). Excised human skin absorption of 14C-PBO at 100 µg/cm2 was determined to be 7% (n=9). Excised rat skin absorptions of permethrin at 2.25, 20, and 200 µg/cm2 were found to be 20, 18, and 24%, respectively (n=6 per dose), approximately 10-fold higher than human skin absorption. Excised rat skin absorption of PBO was also higher (35%) than the value obtained for human skin by a factor of about 5.