Thomas Osimitz - Academia.edu (original) (raw)

Papers by Thomas Osimitz

Journal of toxicology and environmental health, May 1, 2013

Postapplication exposure assessment related to indoor residential application of pesticide produc... more Postapplication exposure assessment related to indoor residential application of pesticide products requires consideration of product use information, application methods, chemical-specific deposition, time-dependent availability and transferability of surface residues, reentry time, and temporal location and macro- and microactivity/behavior patterns ( Baker et al., 2000 ). Children&amp;amp;amp;amp;amp;#39;s mouthing behavior results in potential postapplication exposure to available pesticides in treated microenvironments through the nondietary ingestion route, in addition to the dermal or inhalation routes. Children&amp;amp;amp;amp;amp;#39;s activities and associated behaviors may result in multiple or repeat contact of dermal areas (clothed and unclothed body areas and hands) with treated surfaces, or surfaces that may have indirect sources of residues. Further, some surfaces contacted may have transferable pesticide residues and others may not. Transfer of residues from the indoor residential environment to the dermal surface (e.g., hands) of an individual has been assumed to be linear as a function of time and number of contacts. However, studies suggest that this transfer process to the hands and other body areas may be rapidly saturable. In the most recent U.S. Environmental Protection Agency (EPA), Office of Pesticide Programs (OPP) &amp;amp;amp;amp;amp;quot;Residential Exposure Assessment Standard Operating Procedures&amp;amp;amp;amp;amp;quot; (U.S. EPA, 2012), the input variable for the number of dermal contacts (with treated surfaces) is an exponent, making the relationship nonlinear. Further, removal processes such as hand washing and transfer to untreated surfaces are important to consider. Predictive algorithms for estimating children&amp;amp;amp;amp;amp;#39;s hand-to-mouth-related incidental ingestion exposures post pesticide application have been developed by the EPA/OPP and incorporated into probabilistic models. A review of literature addressing variables used to estimate potential incidental ingestion exposure is presented. Data relevant to input variables for predictive algorithms are discussed, including the results of a multiyear, pesticide transferable residue measurement program conducted by the Non-Dietary Exposure Task Force (NDETF) and the associated distributional characterization for this key variable. Sources of conservative bias in current hand-to-mouth, incidental ingestion exposure estimation and the role of biomonitoring to evaluate predicted exposures are discussed.

The objective of this work was to investigate several aspects of xenobiotic metabolism during pre... more The objective of this work was to investigate several aspects of xenobiotic metabolism during pregnancy in CD(,1) mice. Data on changes in the rates of both cytochrome P-450- and microsomal flavin-containing monooxygenase (MFMO)-dependent xenobiotic oxidations and on the influence of polyamines on xenobiotic monooxygenations are reported. The specific activity of MFMO-dependent N,N-dimethylaniline N-oxidase was unchanged in the kidney, liver, lung, and uterus during pregnancy. Placental activity increased from day 12 of gestation to levels 50 per cent that of maternal liver by day 18 of gestation indicating that MFMO may represent an important xenobiotic-metabolizing enzyme in the placenta. Specific activities of hepatic microsomal aminopyrine-, carbaryl-, and nicotine demethylase, 7-ethoxycoumarin deethylase, and aldrin epoxidase were lower in pregnant mice (days 12 and 18 of gestation) than in nonpregnant females. In contrast, there was no pregnancy-related change in the specific activity of the hepatic microsomal dearylase towards the pesticides EPN and parathion or in the specific content of cytochrome P-450. The polyamines; spermine, spermidine, and putrescine significantly stimulated rates of in vitro oxidation of aldrin, EPN, 7-ethoxycoumarin, and parathion in hepatic microsomes from nonpregnant mice. Spermidine caused a greater relative stimulation of in vitro aldrin oxidation in microsomes from pregnant mice than in microsomes from nonpregnant mice. An examination of the mechanism of spermidine enhancement of aldrin oxidation revealed that spermidine greatly stimulates microsomal NADPH oxidation and the reduction of cytochrome P-450.Ph.D.PharmacologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/160009/1/8412220.pd

Annual Symposium on Computer Application in Medical Care, Nov 9, 1988

TOXPERT is an artificial intelligence based system used to model product safety, toxicology (TOX)... more TOXPERT is an artificial intelligence based system used to model product safety, toxicology (TOX) and regulatory (REG) decision processes. An expert system shell uses backward chaining rule control to link “marketing approval” goals to the type of product, REG agency, exposure conditions and TOX. Marketing risks are primarily a function of the TOX, hazards and exposure potential. The method employed differentiates between REG requirements in goal seeking control for various types of products. This is accomplished by controlling rule execution by defining frames for each REG agency. In addition, TOXPERT produces classifications of TOX ratings and suggested product labeling. This production rule system uses principles of TOX, REGs, corporate guidelines and internal “rules of thumb.” TOXPERT acts as an advisor for this narrow domain. Advantages are that it can make routine decisions freeing professional's time for more complex problem solving, provide backup and training.

Acta horticulturae, Jul 1, 2017

Reports of dermatitis and respiratory reactions associated with use of pyrethrin-containing produ... more Reports of dermatitis and respiratory reactions associated with use of pyrethrin-containing products have been described in the medical literature over the last century. The Pyrethrins Joint Venture has responded in several ways. Using knowledge of pyrethrum chemistry and an evidence-based analysis of literature, we assessed whether pyrethrins induce immunologic contact urticaria (ICU) or allergic contact dermatitis (ACD). Our interpretation suggests that no reports presented in the literature fulfill the criteria for either ICU or ACD. Similarly, our assessment of the published data does not indicate that people with asthma or other evidence of airway hypereactivity are unusually sensitive to pyrethrins. Following a review of reports to North American Poison Control Centers (2001-2003), despite extensive use, incidents with reports of moderate or major adverse effects were rare. The data suggest that asthmatics and people sensitive to ragweed (Ambrosia artemisiifolia) are not unusually sensitive to pyrethrins/piperonyl butoxide (PY/PBO). In view of their widespread use, the data indicate that PY/PBO products can be used with a relatively low risk of adverse effects. The objectives of the Pyrethrums Stewardship Program (PSP) were to investigate consumer exposures to pyrethrin-containing products and evaluate the possible association between use and adverse events. Incidents in which the subject reported at least one dermal or respiratory symptom of minor or greater outcome severity were included in the PSP. Of 531 cases (reports of human exposure to a pyrethrins-containing insecticide) received during 2014, 221 cases involving 177 exposed symptomatic individuals qualified for inclusion in the PSP. Total release foggers were the predominant product type. The majority of the products contained pyrethroids in addition to pyrethrins. Non-specific irritation to the respiratory tract (i.e., cough/choke) was the most commonly reported symptom. Almost 88% of exposed individuals claimed outcomes of minor severity; the remainder claimed moderate effects. Ninety percent of all completers were managed outside of a health care facility (generally at home), further underscoring the minor severity of effects associated with the exposures. No cases of major severity or deaths were reported. Of 177 eligible exposed individuals who were contacted by phone, 50 individuals (with 46% reporting a positive allergy status and 14% a positive asthma status), upon their consent, completed an enhanced questionnaire that probed circumstances of and results from exposure. Assistance with diagnostic patch and prick testing under physician oversight was offered, but no individual chose to participate. None of the data collected to date suggest that pyrethrin-containing products pose a significant risk of serious dermal and/or respiratory reactions to individuals with or without asthma and allergies.

Toxicological Sciences, Jan 10, 2019

The nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice bu... more The nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice but not in Wistar rats. Recently, based on findings of a Pathology Working Group involving an expert panel of pathologists, it was concluded that permethrin increased liver tumors at 2500 and 5000 ppm in female mice, but no treatment-related tumorigenic response occurred in male mice at dose levels examined in the 2-year bioassay. To evaluate a possible mode of action (MOA) for the permethrin female CD-1 mouse hepatocellular tumors, a number of investigative studies were conducted. In time-course studies in female CD-1 mice, permethrin increased relative liver weight and enhanced hepatocyte proliferation within 1 week. Treatment with permethrin resulted in marked increases in CYP4A enzyme activities and mRNA levels, but only slightly increased CYP2B markers, suggesting that permethrin primarily activates the peroxisome proliferator-activated receptor alpha (PPARα) and to a much lesser extent the constitutive androstane receptor. The effects of permethrin on relative liver weight, hepatocyte proliferation and CYP4A enzyme activities and mRNA levels were dose-dependent and were reversible within 5 weeks after cessation of treatment. The hepatic effects of permethrin observed in wild-type female mice were markedly reduced in PPARα knockout female mice. These results demonstrate that the MOA for hepatocellular tumor formation by permethrin in female mice involves activation of PPARα resulting in a mitogenic effect. The MOA for permethrin-induced mouse liver tumor formation due to PPARα activation is considered to be not plausible for humans. This conclusion is strongly supported by available epidemiological data for permethrin.

Pesticide Biochemistry and Physiology, Jun 1, 1985

Pregnancy-related changes in oxidative metabolism of several xenobiotics including pesticides wer... more Pregnancy-related changes in oxidative metabolism of several xenobiotics including pesticides were examined in the hepatic microsomes of CD, mice. The effect of pregnancy on hepatic microsomal cytochrome P-450~catalyzed substrate oxidation was found to be dependent upon the type of reaction examined. Not all substrates undergoing the same reaction showed identical changes during pregnancy. Those enzyme activities which exhibited a decline in specific activity during pregnancy generally exhibited no change in total hepatic capacity. Enzymes posting no change in specific activity throughout gestation generally showed large increases in total hepatic activity. Phorate S-oxidation was catalyzed by both microsomal flavin-containing monooxygenase (MFMO) and cytochrome P-450. Moreover, there was no pregnancy-related change in either MFMO or total enzymatic (MFMO plus cytochrome P-450) phorate S-oxidation. 6 1985 Academic Press. Inc. MATERIALS AND METHODS Chemicals. Aldrin (recrystallized) was obtained from City Chemical (New York, N.Y.). The pesticides carbaryl, EPN (Oethyl-O-p-nitrophenyl phenylphosphonothioate), nicotine, parathion, and phorate were purchased from Chem Service (West Chester, Pa.), and were of the highest purity available. All other chemicals were of 328 0048-3575185 $3 .OO

Journal of toxicology, 1994

This study analyzed 9,086 human exposures involving N,N-diethyl-m-toluamide--containing insect re... more This study analyzed 9,086 human exposures involving N,N-diethyl-m-toluamide--containing insect repellents that were reported to Poison Control Centers from 1985-1989. Nearly two-thirds of those exposed had no adverse effects or only experienced minor symptoms that resolved rapidly. Symptoms were more likely to occur after ocular or inhalation exposures and least likely to occur if the product was ingested. The only reported death occurred in a patient who suicidally ingested 8 oz of an insect repellent containing N,N-diethyl-m-toluamide. Five patients may have experienced a serious or potentially life-threatening effect but the poison center record did not provide unequivocal substantiation of the effect or clearly establish N,N-diethyl-m-toluamide as the causative agent. From the analysis of those patients calling Poison Control Centers, it appears the risk of serious medical effects with the labeled use of N,N-diethyl-m-toluamide-containing insect repellents is low in comparison with its reported annual use by about 30% of Americans. For patients contacting Poison Control Centers, the occurrence of adverse effects appears to be related to the route of exposure rather than age or gender of the patient or the concentration of N,N-diethyl-m-toluamide in the product.

Journal of Toxicology and Environmental Health, Part A

Toxicological Sciences, 2020

The assessment of potentially sensitive populations is an important application of risk assessmen... more The assessment of potentially sensitive populations is an important application of risk assessment. To address the concern for age-related sensitivity to pyrethroid insecticides, life-stage physiologically based pharmacokinetic (PBPK) modeling supported by in vitro to in vivo extrapolation was conducted to predict age-dependent changes in target tissue exposure to 8 pyrethroids. The purpose of this age-dependent dosimetry was to calculate a Data-derived Extrapolation Factor (DDEF) to address age-related pharmacokinetic differences for pyrethroids in humans. We developed a generic human PBPK model for pyrethroids based on our previously published rat model that was developed with in vivo rat data. The results demonstrated that the age-related differences in internal exposure to pyrethroids in the brain are largely determined by the differences in metabolic capacity and in physiology for pyrethroids between children and adults. The most important conclusion from our research is that, ...

Current Opinion in Toxicology, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Biochemical and Biophysical Research Communications, Dec 1, 1982

Toxicological Sciences, 2019

To address concerns around age-related sensitivity to pyrethroids, a life-stage physiologically b... more To address concerns around age-related sensitivity to pyrethroids, a life-stage physiologically based pharmacokinetic (PBPK) model, supported by in vitro to in vivo extrapolation (IVIVE) was developed. The model was used to predict age-dependent changes in target tissue exposure of 8 pyrethroids; deltamethrin (DLM), cis-permethrin (CPM), trans-permethrin, esfenvalerate, cyphenothrin, cyhalothrin, cyfluthrin, and bifenthrin. A single model structure was used based on previous work in the rat. Intrinsic clearance (CLint) of each individual cytochrome P450 or carboxylesterase (CES) enzyme that are active for a given pyrethroid were measured in vitro, then biologically scaled to obtain in vivo age-specific total hepatic CLint. These IVIVE results indicate that, except for bifenthrin, CES enzymes are largely responsible for human hepatic metabolism (>50% contribution). Given the high efficiency and rapid maturation of CESs, clearance of the pyrethroids is very efficient across ages, l...

Journal of the American College of Toxicology, Nov 1, 1992

Toxicology Letters, Aug 1, 1983

This chapter outlines the safety assessment of butoxide, its uses, and studies. Piperonyl butoxid... more This chapter outlines the safety assessment of butoxide, its uses, and studies. Piperonyl butoxide (PBO) is an insecticide synergist produced from the condensation of the sodium salt of (2-butoxyethoxy) ethanol and the chloromethyl derivative of hydrogenated safrole. PBO inhibits the mixed function oxidase system of insects, thereby reducing the oxidative breakdown of other pesticides like pyrethrum and the synthetic pyrethroids, thus rendering it inactive; the result is that higher levels of the insecticide remain in the insect and are available to exercise their lethal effect on the insect. PBO enhances the pesticidal activity of a given level of active ingredient, thus promoting reduced use of the pesticide. PBO has been tested in dogs, mice, rats, and rabbits for subchronic toxicity. Most recent studies indicate that PBO is generally of low acute toxicity to animals, but mildly irritating to the eye and skin. Although no systematic epidemiology studies have been conducted on PBO-exposed individuals, no evidence suggests that PBO has resulted in any significant adverse effects to human health.

Human & Experimental Toxicology, Jun 1, 1998

The oncogenicity of Piperonyl butoxide (PBO) has been studied in the mouse and rat. CD-1 mice wer... more The oncogenicity of Piperonyl butoxide (PBO) has been studied in the mouse and rat. CD-1 mice were administered PBO in the diet at target doses of 0, 30, 100 and 300 mg/kg/day for 79 weeks and Sprague ± Dawley rats 0, 30, 100 and 500 mg/kg/day for 104/105 weeks. 2 At termination of the study in the mouse there was evidence of increased liver weights and an increased incidence of eosinophilic adenomas at 100 and 300 mg/kg/day in males and 300 mg/kg/day in females. 3 In rats there was increased liver weights at 100 and 500 mg/kg/day associated with hepatocyte hypertrophy in both male and female rats. There was no increased incidence of neoplasia at any site. Hypertrophy and hyperplasia of thyroid follicles was observed at 500 mg/kg/day in both sexes. 4 The observations re¯ect the expected changes related to the induction of the mixed function oxygenase group of enzymes. In the mouse the increased incidence of eosinophilic adenomas is not considered relevant for human risk evaluation.

Journal of toxicology and environmental health, Feb 22, 2022

ABSTRACT Quaternary ammonium compounds (QACs) or quats are a large class of antimicrobial chemica... more ABSTRACT Quaternary ammonium compounds (QACs) or quats are a large class of antimicrobial chemicals used in households and institutions as sanitizers and disinfectants. These chemicals are utilized as food processing sanitizers, algicides, in the process of water treatment, and preservatives in cosmetics. The aim of this study was to determine an Adverse Outcome Pathway (AOP) whereby two widely used QACs, alkyl dimethyl benzyl ammonium chloride (ADBAC) and didecyl dimethyl ammonium chloride (DDAC), may result in respiratory tract and gastrointestinal tract effects. When inhaled or ingested, these QACs are incorporated into the epithelial cell membrane at the point of contact. With sufficient dosage, the epithelial membrane is disrupted, reducing its fluidity, and releasing cellular contents. Further, ADBAC and DDAC might disrupt mitochondrial functions leading to decreased ATP production. Both events might lead to cell death, either attributed to direct lysis, necrosis, or apoptosis. Pro-inflammatory mediators are recruited to the tissue, inducing inflammation, edema, and excess mucus production. The primary tissue-level adverse outcome is epithelial degeneration and dysplasia. Most important, no apparent metabolism or distribution is involved in QAC action. Based upon this knowledge, it is suggested to replace default Uncertainty Factors for risk assessments with a set of Data Derived Extrapolation Factors.

Journal of Toxicology and Environmental Health, 1985

Propylene is hepatotoxic to male Charles River COBS Sprague-Dawley rats pretreated with polychlor... more Propylene is hepatotoxic to male Charles River COBS Sprague-Dawley rats pretreated with polychlorinated biphenyls (PCB: Aroclor 1254). Four-hour inhalation exposure to 50,000 ppm propylene increased liver weight/body weight ratios and elevated serum enzyme activities in PCB-pretreated animals. Hepatic microsomal cytochrome P-450 content of PCB-pretreated rats dropped profoundly during propylene exposure and remained depressed for at least 24 h. In addition, PCB-pretreated, propylene-exposed rats exhibited a decrease in the specific activity of hepatic microsomal aniline hydroxylase. However, there was no change in activities of either hepatic microsomal aminopyrine demethylase or glucose-6-phosphatase. Propylene exposure of rats pretreated with beta-naphthoflavone (BNF), phenobarbital (PB), or a mixture of BNF and PB was not hepatotoxic. However, there was, in these animals, a substantial decline in hepatic microsomal cytochrome P-450 levels 24 h after the start of propylene exposure. Hence, the propylene-dependent process resulting in hepatic cytochrome P-450 destruction is qualitatively or quantitatively different from the process that causes acute hepatotoxicity. Preexposure fasting had no effect on the hepatotoxicity resulting from a 4-h exposure of PCB-pretreated rats to 50,000 ppm propylene. Administration of SKF-525A to PCB-pretreated rats immediately prior to propylene exposure completely prevented elevations in serum enzyme activities and liver weight/body weight ratios. In vitro incubation of hepatic microsomes prepared from either BNF-, PB-, or PCB-pretreated rats with an atmosphere of 20% propylene/80% air produced in NADPH-dependent decrease in cytochrome P-450 content. These results suggest that PCB pretreatment is a prerequisite for propylene hepatotoxicity in the rat. Cytochrome P-450-dependent bioactivation of propylene is associated with this hepatotoxicity, but further studies are needed to characterize the mechanism of the PCB-propylene interaction.

Inhalation Toxicology, Jan 2, 2019

Seventy-one percent of US households purchase air care products. Air care products span a diverse... more Seventy-one percent of US households purchase air care products. Air care products span a diverse range of forms, including scented aerosol sprays, pump sprays, diffusers, gels, candles, and plug-ins. These products are used to eliminate indoor malodors and to provide pleasant scent experiences. The use of air care products can lead to significant benefits as studies have shown that indoor malodor can cause adverse effects, negatively impacting quality of life, hygiene, and the monetary value of homes and cars, while disproportionately affecting lower income populations. Additionally, studies have also shown that scent can have positive benefits related to mood, stress reduction, and memory enhancement among others. Despite the positive benefits associated with air care products, negative consumer perceptions regarding the safety of air care products can be a barrier to their use. During the inaugural Air Care Summit, held on 18 May 2018 in the Washington, DC, metropolitan area, multidisciplinary experts including industry stakeholders, academics, and scientific and medical experts were invited to share and assess the existing data related to air care products, focusing on ingredient and product safety and the benefits of malodor removal and scent. At the Summit's completion, a panel of independent experts representing the fields of pulmonary medicine, medical and clinical toxicology, pediatric toxicology, basic science toxicology, occupational dermatology and experimental psychology convened to review the data presented, identify potential knowledge gaps, and suggest future research directions to further assess the safety and benefits of air care products.