Citations below refer to Dr. Bogen's publications
Allergic Contact Dermatitis Risk Assessment
U.S. Wearable Technology Manufacturers (2013-2017)
Major manufacturers of wearable technology consumer products hired Exponent to evaluate likely causal factors and risks of allergic contact dermatitis (ACD) elicited by sustained dermal contact with such products being designed and/or marketed. Exponent work in this area was precipitated by incidents of ACD suspected of having been caused by dermal contact with specific products that had received wide publicity, by manufacturers who retained Exponent to identify potential causal factors. Exponent has also been retained during product development to prevent or reduce the likelihood of similar ACD incidents and associated adverse product publicity. With Dr. Bogen's initial input on test design, Exponent performed leach tests in simulated sweat at elevated temperature (analogous to European Union Nickel Directive (EN 1811) testing requirements for leaching of nickel from consumer products) followed up by chemical analysis of leached metals and organics, which he initially assessed for potential or known sensitization capacity. For each sensitizer Dr. Bogen identified, he directed in-house efforts to accumulate available related ACD-relevant literature, including published human clinical patch test data with a focus on those studies that involved patch test series conducted at different applied dermal loads of each test chemical. Since 2014, using this accumulating data base, Dr. Bogen explored the idea of using such available clinical patch test data as a basis for quantitative assessment of ACD elicitation risk (ACDER) in relation to defined dermal loads of specific sensitizers. Previous similar analyses of such data for certain human sensitizers provided some indication (and in the case of nickel, a clear indication) that such quantitative ACDER assessment is feasible. Dr. Bogen's analysis of these data revealed not only that this conclusion is indicated for all three metallic human sensitizers and all five organic human sensitizers for which a substantial set of clinical patch test data had been published, but that all of these sensitizers exhibited a similar type of ACDER response pattern in relation to applied dermal load. Specifically, each sensitizer exhibited a lognormal ACDER response pattern with statistically similar “slope” (i.e., geometric standard deviation) values but with different, sensitizer-specific “potency” (i.e., geometric mean dermal load) values. Dr. Bogen presented these results at the 2017 Society of Toxicology annual meeting, and subsequently published a corresponding paper (Bogen & Garry 2017 Risk Anal, in press). While earlier approaches (e.g., guinea pig maximization, mouse local lymph node assay [LLNA], relative in vitro reactivity, and quantitative structure-activity [QSAR]) have been developed to classify relative potency for the first (sensitization) phase of the two-phase ACD (i.e., delayed, or Type IV hypersensitivity) immune reaction, the approach I developed described above is a fully quantitative approach to ACD risk assessment for multiple sensitizers and is the first published approach to assess risk for the second (elicitation) phase of ACD that is the focus of EN 1811.
Benzene from Parts-Washing and Gasket-Removal Solvents
Litigation Support (2007–2009, 2017)
Dr. Bogen led the development of approaches to estimate average inhalation, dermal, and total benzene exposures for each of several plaintiffs who incurred such occupational exposures during parts washing, using: a) data on historical concentrations of benzene in recycled Safety-Kleen 105 solvent (SKS); b) models he fit to measures of benzene and toluene volatilization from SKS over time; c) his statistical analysis of paired measurements of benzene and other aromatic compounds in SKS and in worker air during parts-washing activities that were measured by the National Medical Advisory Service at 16 parts washing facilities; d) a collaborative application of the universal functional activity coefficient (UNIFAC) thermodynamic equation-of-state approach to estimate activity as a function of mole fraction for non-ideal binary solutions volatilized from an SKS-like hydrocarbon blend; and e) a two-process model of benzene uptake from dermally contacted SKS that he developed using results from IRB-approved experiments he designed in which rates of SKS uptake into human skin in vivo were measured—work that later was published (Sheehan et al. 2010, 2017 Risk Anal; Bogen & Sheehan 2014 Risk Anal).
Dr. Bogen subsequently applied his two-process dermal uptake model to derive estimates of the amount of benzene dermally absorbed by a plaintiff in another litigation matter involving occupational exposure to a different benzene-containing solvent during brushing and scraping activity associated with gasket-removal tasks.
Furfuryl Alcohol Cancer Risk
U.S. Food Manufacturer (2016)
Dr. Bogen derived no-significant risk level (NSRL) values for furfuryl alcohol, identified in 2016 as a carcinogen under California Proposition 65, based on observations that in rats and mice exposed to this chemical for two years by inhalation National Toxicology Program (NTP) cancer bioassay studies, there were (albeit marginally) elevated rates of historically rare nasal tumors in male rats and rates elevated above historically rare kidney tumors in male mice. NSRL values for each elevated tumor type were based on my analysis of corresponding NTP bioassay dose-response data using U.S. Environmental Protection Agency (EPA) Benchmark Dose software, addressing certain challenging subtleties contained in NTP-reported time-to-tumor data from this bioassay.
Tert-Butyl Alcohol Carcinogenicity
American Petroleum Institute (API) (2016)
Dr. Bogen was retained by API to prepare and to submit to the U.S. Environmental protection Agency (EPA) IRIS TBA public docket a response to that Agency’s IRIS Toxicology Review of tert-butyl alcohol (TBA). His comments “Technical Comments Submitted to U.S. EPA Docket ID No. EPA-HQ-ORD-2013-0111 Concerning the IRIS Draft Toxicological Review of tert-Butyl Alcohol: Relevance of Rat Kidney and Mouse Thyroid Tumors” (24 pp.) were submitted on July 15, 2016, and later were reviewed by API (Aug 8, 2017).
Dose Response Arsenic-Induced Cytotoxicity
Electric Power Research Institute (EPRI) (2015)
Dr. Bogen devised and obtained EPRI funding for a ~$250K collaborative research project with Prof. Samuel Cohen at the University of Nebraska Medical Center to investigate high-resolution low-dose dose-response for reduced viability of cells exposed to inorganic arsenic in vitro. This work subsequently was published (Bogen et al. 2017 Toxicol Reports).
Formaldehyde Exposure AND CANCER RISK
U.S. Flooring Manufacturer (2014-2016)
Exponent was retained to assist a major U.S. manufacturer of formaldehyde-emitting laminated flooring in product-related meetings with the U.S. Consumer Product Safety Commission and to help prepare for product-related litigation. To address potential exposure concerns, the manufacturer had tested the largest-ever set of measured formaldehyde emission rates from samples of new laminated flooring, using standard small chamber test methods; after obtaining residents’ consent, this manufacturer also gathered the largest-ever set of in-home measures of formaldehyde in air and corresponding small-chamber-test measures of rates of formaldehyde emission rates from samples of previously installed laminated flooring. Dr. Bogen supervised the analysis of this combined data set at various stages of data acquisition; fit the final combined set of measured formaldehyde emission rates in relation to time since flooring installation; and, using home survey data also obtained, developed a stochastic flooring-attributable household formaldehyde concentration model and implemented this model using Monte Carlo methods to calculate corresponding variability distributions of inhaled formaldehyde and associated potential cancer risk. This work was later published (Sheehan et al. 2017 Risk Anal, in press).
Prop 65 Compliance for Chemicals Migrated from Paperboard Food Packaging Products
American Forest and Paper Association (AF&PA) (2012–2015)
Exponent developed and delivered for use by AF&PA members an Excel®-based Computer Tool for determining maximum concentrations that comply with California Proposition 65 (Prop 65) for a wide array of chemicals that all are listed as reproductive toxins and/or carcinogens under Prop 65 and that may be present in an array of different types of paperboard products manufactured by AF&PA members for food/beverage packaging applications. Dr. Bogen designed the physico-chemical regression modeling approach that was, in a competitive review process, selected by AF&PA to serve as the basis for developing this Tool. He derived the entire suite of empirically based physico-chemical regressions and temperature-dependent models of chemical-specific vapor pressure that the Tool incorporates to predict mass-transport of chemicals from paperboard to contacted food later ingested, to skin, and to inhaled air. Dr. Bogen collaborated with Exponent colleagues to have these models applied by the Tool to product-category-specific multi-route exposure scenarios for consumers and workers who contact such products and/or ingest food contained in such products. The Excel®-based computer Tool delivered to AF&PA is now used by its members to evaluate Prop 65 compliance of existing and proposed paperboard packaging products, and periodically has been updated to support a current total of 123 chemicals that may be present in paperboard food/beverage packaging products. Dr. Bogen is lead author of one and co-author of another manuscript prepared for journal submission describing modeling approaches and applications of this Tool.
Human Biokinetic Model for Nickel
Minnesota Medical Device Manufacturer, and Nickel Producers Environmental Research Association (NiPERA) (2012–2018)
Dr. Bogen's services at Exponent were retained by a Minnesota medical device manufacturer to do a biokinetic analysis of nickel release from each of a series of nitinol cardiac plug medical devices in vivo and in vitro. To support this effort for each cardiac plug device in the series evaluated by Exponent, he first incorporated and modified previously published human biokinetic models for nickel to formulate a new model that he fit to previously published human biokinetic data for nickel, and implemented this model in Mathematica® software. Then, for each device evaluated, he modeled corresponding in vitro Ni-release data obtained experimentally by Exponent, and used his human biokinetic model to predict rates of nickel release expected to occur after in vivo surgical implantation of that device. His services at Exponent were subsequently retained by NiPERA to further develop and validate this human biokinetic model for nickel using additional unpublished human data funded by NiPERA, to apply this model to evaluate individual occupational exposures to nickel, and in 2018 to co-author a related manuscript to be submitted for journal publication.
Lead Exposure Characterization Under
Prop 65
Litigation Support and California Chamber of Commerce (2012–2016)
At Exponent Dr. Bogen provided litigation support in several matters concerning lead exposure in the context of compliance with California Proposition 65 (Prop 65). He did this using Mathematica® software he developed initially to implement a human biokinetic model for lead published by Leggett in 1993, which predicts age-specific blood lead levels over time in relation to user-specified, time-specific, oral and/or inhalation exposure(s) to defined amounts of lead, e.g., from ingesting a toy, handling lead-containing brass, etc. He later implemented in Mathematica® software an update of the 1993 Leggett biokinetic lead model, called the Leggett+ model (a human physiologically-based pharmacokinetic [PBPK] model for lead), which was released in 2013 by the California Environmental Protection Agency, Office of Environmental Health Hazards Assessment (OEHHA). Subsequently, Dr. Bogen was retained by the California Chamber of Commerce to evaluate the accuracy and consistency of the OEHHA Leggett+ model, which had been implemented by OEHHA in MatLab® software. This work identified a coding error in initially released Leggett+ software that later was corrected by OEHHA.
Dose Response for Arsenic-Induced Human Lung Cancer
Arsenic Task Force (2013–2014)
Dr. Bogen at Exponent collaborated on an assessment of low-dose linearity exhibited in epidemiological data on arsenic-associated lung cancer in Taiwan (Bogen et al. 2014, SOT presentation). He was also funded by the Arsenic Task Force to support a related manuscript he had previously initiated to address mathematical and biological problems raised by the National Research Council (2009) Science and Decisions report recommendation to apply default low-dose linear assumptions for noncancer endpoints. The resulting published paper (Bogen 2016 Risk Anal) received a Society for Risk Analysis Best Paper of the Year award in 2016.
Anthraquinone cancer risk
Paperboard Product Manufacturer (2008–2014)
Dr. Bogen authored an Exponent report deriving a California Proposition 65 (Prop 65) No Significant Risk Level (NSRL) for anthraquinone (AQ), which was listed in 2007 as a Prop 65 chemical carcinogen based on National Toxicology Program (NTP) cancer bioassay results indicating that lifetime dietary exposure to AQ can elevate liver tumors in male and female mice and kidney tumors in female rats. He also analyzed NTP bioassay results indicating that AQ very clearly and potently reduced the incidence of mononuclear cell leukemia in male and female rats, and by Monte Carlo methods showed that overall AQ has a net anti-tumorigenic effect in rodents, results subsequently published (Bogen 2011, Dose-Response). Dr. Bogen later was lead contributor to an Exponent margin-of-exposure evaluation of cancer risk from dietary AQ cancer hazard, in the context of regulatory assessment by one or more European Union (EU)-affiliated regulatory or advisory organizations concerning whether AQ residues in various paperboard packaging materials are sufficiently low to meet EU regulatory requirements.
Neurotoxicity Risk of Zinc from Nasal Gel
Arizona Pharma Manufacturer (2012)
At Exponent Dr. Bogen was retained by an Arizona manufacturer of a zinc-containing nasal cold-remedy gel to predict the likelihood of a key neurotoxic endpoint (anosmia), involving olfactory receptor neuron (ORN) cells located relatively high in the nasal cavity that are required for the sense of smell, after single or repeated use of the gel product applied in a manner consistent with package instructions. To do this, he developed a realistic mathematical model of the human nasal cavity and mucous-covered surface epithelium, which I adapted from a highly detailed (>500,000-vertex) 3D anatomical model published in 2009, to represent an approximation of nasal cavities of a total of 30 male and female patients having a wide age range. The adapted model was designed to allow efficient application of a grid-based surface-diffusion algorithm he implemented in Mathematica® software to predict zinc-ion diffusion into mucosal fluid covering the rather complex surface geometry of the human nasal cavity (Figure 1). To predict ORN loss likelihood, he combined this model with a) data obtained from experiments I conducted to quantify the droplet size distribution of gel dispensed from the product dispenser, b) data literature on the location and dispersion of nasally deposited gel, and c) a toxic-load model he fit to published data on olfactory neurotoxicity in relation to zinc concentration and exposure duration. His resulting 60+-page technical report concluded that there is no substantial risk of ORN injury from local-droplet deposition of dispensed gel under conditions of normal product use (Figure 1).
Figure 1. (Left panel) Lateral-wall view of the nasal section model used to implement an efficient diffusion-simulation algorithm, shown together with areas assumed to represent olfactory epithelium (red) and gel deposition (blue). (Right panel) Simulated diffusion and flow of elevated Zn(+2)-ion concentration C, plotted on normalized, logarithmic scale as Cnorm = log10(100 C/Co), after a conservatively placed nasal gel administration, relative to the maximum Zn(+2) concentration (Co = 34.7 mM) in the gel (red) at 3.3–60 min after gel administration, assuming a conservative mucociliary clearance rate of 1.0 mm/min.
Cancer risk from Household MTBE Exposure After Gasoline storage Tank Leak
Expert Toxicologist, Maryland litigation (2012)
At Exponent Dr. Bogen was retained as a designated expert toxicologist in the civil lawsuit Ayala et al. v. The Carroll Independent Fuel Company et al. before the Circuit Court for Frederick County, Maryland, concerning alleged chronic human exposures primarily to the gasoline additive (fuel oxygenate) chemical methyl tert-butyl ether (MTBE) in groundwater. He prepared a 328-page expert report providing opinions addressing MTBE absorption, distribution, metabolism, and excretion; genotoxicity of MTBE and its metabolites; tumorigenicity of MTBE and its metabolites; modes of action for tumors associated with exposure to MTBE and/or its metabolites; and quantitative characterizations of MTBE cancer potency designed to support risk-based MTBE-related decisions in different (e.g., protective/regulatory vs. predictive/litigation) contexts. The case was settled just prior to my scheduled deposition, and Dr. Bogen subsequently co-authored an adaptation of his expert report as a 134-page scientific article (Bogen & Heilman 2015 Crit Rev Toxicol).
Diethanolamine & diethanolamides Cancer Risk
U.S. Manufacturer, & U.S. Manufacturer Association (2012–2013)
Dr. Bogen was lead author of Exponent technical reports deriving California Proposition 65 (Prop 65) No Significant Risk Level (NSRL) values for diethanolamine and cocamide diethanolamine condensate, which in 2012 were identified as Prop 65 carcinogens under based on observation of clearly elevated liver tumors and marginally elevated kidney tumors in mice (but not rats) exposed chronically to dermally administered doses of these chemicals in National Toxicology Program (NTP) cancer bioassay studies. Based on his detailed analysis of available pertinent dose-response and carcinogenic mode-of-action (MOA) data, different NSRL levels were proposed using alternative genotoxic and nongenotoxic MOA assumptions, the latter being concluded as more likely in view of available mechanistic evidence.
4-MEI Cancer Risk
American Beverage Association, International Technical Caramel Association (2011–2012)
At Exponent, Dr. Bogen authored two technical reports addressing the chemical 4-methylimidazole (4-MEI), which is used in chemical manufacturing and is found in certain food products such as caramel food coloring, and which was in 2008 listed as a carcinogen under California Proposition 65 (Prop 65), based on National Toxicology Program (NTP) cancer bioassay results indicating clearly elevated incidence of lung tumors in male and female mice exposed chronically by diet. 4-MEI. In 2011, the California Environmental Protection Agency (CalEPA) Office of Environmental Health Hazard Assessment (OEHHA) adopted a Prop 65 no-significant risk level (NRSL) for 4-MEI of 16 micrograms/day (ug/day), under a default genotoxic MOA assumption in view of uncertainty concerning the mechanism of 4-MEI-induced lung tumors in mice. Based on a review and analysis of published data bearing on 4-MEI mode of action (MOA), Dr. Bogen's reports proposed a novel, highly specific, nongenotoxic, enzyme-mediated MOA for mouse lung tumors induced by 4-MEI, and a corresponding no-significant risk level (NRSL) of 1,900 ug/day for 4-MEI associated with this alternative MOA hypothesis.
Human PBPK Models for Malathion, Dimethoate
Cheminova, FMC Corp. (2011–2017)
By adapting previously published biokinetic and physiologically based pharmacokinetic models of the organophosphate pesticide malathion in humans, Dr. Bogen at Exponent developed a new human PBPK model for malathion, implemented this new model in Mathematica® software, and validated this model by fitting it to several data sets involving humans exposed to malathion. He subsequently applied the new model to explore the relationship between applied dermal load and dermal malathion absorption exhibited in a large set of published data obtained using human volunteers dermally exposed to malathion (Bogen & Singhal 2016 J Environ Sci Health B). Dr. Bogen subsequently developed and implemented in Mathematica® a human PBPK model of the organophosphate pesticide dimethoate.
Post-BP-Spill Inhalation & Dermal Exposure
British Petroleum (2011)
Dr. Bogen contributed to Exponent assessments of dermal and respiratory exposures that arose from the BP oil spill, by developing and applying an empirical approach using real-time wind-direction data to show that real-time air monitoring data collected during the event were inconsistent with hypothesized event-caused increases in concentrations of onshore event-related chemicals measured in air. He also contributed to assessments of dermal exposures to event-related beach-deposited chemicals, by deriving chemical-specific permeability coefficients and applying these to estimate corresponding chemical exposures associated with conservative dermal contact scenarios.
Phthalate exposures from children's products
California Department of Justice (2009)
Dr. Bogen designed and directed a screening-Level hazard assessment for six phthalates under A.B. 1108 (the California Toxic Toy Bill) and California Proposition 65 (Prop 65) prepared by Exponent for the California Department of Justice (CalDOJ) (Bogen & Goswami, Exponent technical report to CalDOJ, May 9, 2009, 96 pp.). For specified categories of children's products, this detailed assessment identifies upper bounds on product-category-specific concentrations of specified phthalates that are very likely to comply with Prop 65 requirements, by applying empirically based but (in view of substantial knowledge gaps) substantially conservative assumptions concerning phthalate mass transfer and dermal absorption. These assumptions were not designed, and thus cannot reliably be applied, to identify product-specific phthalate concentrations expected not to comply with Prop 65.
Phthalate & Formaldehyde Exposure from Children’s Playwear and Sleepwear
Expert Toxicologist, California litigation (2008)
At Exponent, Dr. Bogen was retained as Defendant’s expert toxicologist in a California litigation matter, Laurie M. Montanez and Jehan Hughes v. Gerber Childrenswear, concerning dermal exposure to and absorption of phthalate formaldehyde chemicals from tagless labels on children’s playwear and sleepwear clothing. He prepared a related declaration and was deposed in this matter.
Cobalt Biokinetics & Cancer Risk
California Medical Device Manufacturer (2008)
Dr. Bogen was lead author of an Exponent technical report addressing potential FDA regulatory concerns of interest to a California medical-device manufacturer about cobalt and tungsten carbide residues released by its newly designed surgical cutting device. This report incorporated his overview of potential toxicity and cancer risk posed by systemically distributed particulate cobalt residue, and results from his applications of an adaptation of a published human biokinetic model for cobalt that he implemented using Mathematica® software.
Residential Radon Exposure & Cancer Risk
Expert in Radiation Risk, West Virginia litigation (2008)
At Exponent, Dr. Bogen was retained as Defendant’s expert in radiation risk for a West Virginia litigation matter involving elevated residential exposure to radon gas over extended periods of time. To assess potential elevated lung cancer risks associated with residential radon (Rn) exposure using U.S. Environmental Protection Agency methods (U.S. EPA 2003), he implemented those methods using Mathematica® software to calculate EPA-predicted relative risk (RR) of lung cancer above background rates for ever- and never-smoking males and females in relation to age during which residential Rn exposure occurred and measured basement Rn concentration (in units of picoCuries per liter, or pCi/L). This relationship for male ever-smokers is summarized in Figure 2.
Characterization of Asbestos Exposure from Joint Compound
U.S. Manufacturer (2007–2014)
Dr. Bogen contributed to experimental designs for, and provided statistical and modeling analysis of data from, experiments performed to reconstruct historical human exposures to chrysotile asbestos contained historically in joint compound, resulting in a series of publications (Brorby et al. 2011 J Occup Environ Hyg; Bogen et al. 2011 Ann Occup Hyg; Sheehan et al. 2011 and 2014 Ann Occup Hyg; Berman et al. 2012 Ann Occup Hyg; Brorby et al. 2013 Risk Anal).
atmospheric chemical dispersion & toxicity Modeling
Research at LLNL (2005–2007)
Dr. Bogen developed and directed LLNL research directed at better predicting the magnitude by which chemical toxicity threat zones (CTTZs) are likely to be underestimated using commonly applied atmospheric dispersion models (ADMs), which do not account for realistic levels of spatial and temporal concentration fluctuation under urban/outdoor conditions. Widely used for emergency preparation and response, such ADMs rely on Acute Emergency Guideline Level (AEGL) or similar chemical concentration guidelines to map geographic areas potentially affected by corresponding levels of toxic severity (i.e., to map CTTZs). By focusing only on time-weighted average (TWA) chemical concentration, such standard models ignore substantial, random variability in concentration over time and space and so routinely underestimate CTTZ size. Specifically, such models ignore (1) temporal concentration fluctuation for chemicals like hydrogen cyanide (HCN) and hydrogen sulfide having a "toxic load exponent" n that is >1, when acute toxic response R at concentration C over time T is modeled as R ~ (C^n)T (i.e., following a generalized form of Haber's law [see p. 93 ff.]), and (2) spatial concentration heterogeneity that (if measured) is actually observed to occur along contours at which standard models predict constant TWA concentrations. By modeling key relationships exhibited by measured magnitudes of spatiotemporal fluctuation in tracer-gas concentration from urban/outdoor field experiments, Dr. Bogen derived a readily applied method to post-process standard ADM output to correct for its CTTZ-underestimation bias. An illustration of this approach, implemented in collaboration with the National Atmospheric Release Advisory Center (NERAC) at LLNL (Figure 3), showed that such bias may result in up to 20-fold underestimation of CTTZ areas likely to experience potentially lethal exposures after a hypothetical HCN release in an urban area (Bogen & Gouveia (2008, J Haz Mater A).
Figure 3. NARAC-model assessments of chemical toxicity hazard posed by a hypothetical atmospheric dispersion of 1000 kg of hydrogen cyanide (HCN) over a 1-hour period in an urban area in California. An assessment based on current default methodology (left panel) is compared to the assessment obtained by applying the same dispersion model to identical meteorological and release conditions using a modified approach that adjusts for impacts due to expected levels of concentration fluctuation on integrated toxic load (right panel). Both panels show the same ~120-sq-km bounding area on the same scale using the same color scheme to specify AEGL levels of potential toxic severity for a general population including susceptible individuals (red = lethal or life-threatening; orange = serious, irreversible or long-lasting; yellow = transient, non-disabling & reversible). The left panel inset shows with magnified scale the zones predicted to be potentially hazardous using the default approach. Note that the right panel’s orange zone is only slightly bigger than its red zone, and this red (potentially lethal) zone is 20 times larger than the red zone in the left panel. Source: adapted from Fig. 6 of Bogen & Gouveia (2008, J Haz Mater A).