Listeria monocytogenes Dose Response Revisited—Incorporating Adjustments for Variability in Strain Virulence and Host Susceptibility

Evaluations of Listeria monocytogenes dose‐response relationships are crucially important for risk assessment and risk management, but are complicated by considerable variability across population subgroups and L. monocytogenes strains. Despite difficulties associated with the collection of adequate data from outbreak investigations or sporadic cases, the limitations of currently available animal models, and the inability to conduct human volunteer studies, some of the available data now allow refinements of the well‐established exponential L. monocytogenes dose response to more adequately represent extremely susceptible population subgroups and highly virulent L. monocytogenes strains. Here, a model incorporating adjustments for variability in L. monocytogenes strain virulence and host susceptibility was derived for 11 population subgroups with similar underlying comorbidities using data from multiple sources, including human surveillance and food survey data. In light of the unique inherent properties of L. monocytogenes dose response, a lognormal‐Poisson dose‐response model was chosen, and proved able to reconcile dose‐response relationships developed based on surveillance data with outbreak data. This model was compared to a classical beta‐Poisson dose‐response model, which was insufficiently flexible for modeling the specific case of L. monocytogenes dose‐response relationships, especially in outbreak situations. Overall, the modeling results suggest that most listeriosis cases are linked to the ingestion of food contaminated with medium to high concentrations of L. monocytogenes. While additional data are needed to refine the derived model and to better characterize and quantify the variability in L. monocytogenes strain virulence and individual host susceptibility, the framework derived here represents a promising approach to more adequately characterize the risk of listeriosis in highly susceptible population subgroups.     

Risk of Fetal Mortality After Exposure to Listeria monocytogenes Based on Dose-Response Data from Pregnant Guinea Pigs and Primates

One‐third of the annual cases of listeriosis in the United States occur during pregnancy and can lead to miscarriage or stillbirth, premature delivery, or infection of the newborn. Previous risk assessments completed by the Food and Drug Administration/the Food Safety Inspection Service of the U.S. Department of Agriculture/the Centers for Disease Control and Prevention (FDA/USDA/CDC)^{( 1 )} and Food and Agricultural Organization/the World Health Organization (FAO/WHO)^{( 2 )} were based on dose‐response data from mice. Recent animal studies using nonhuman primates^{( 3 , 4 )} and guinea pigs^{( 5 )} have both estimated LD₅₀s of approximately 10⁷ Listeria monocytogenes colony forming units (cfu). The FAO/WHO^{( 2 )} estimated a human LD₅₀ of 1.9 × 10⁶ cfu based on data from a pregnant woman consuming contaminated soft cheese. We reevaluated risk based on dose‐response curves from pregnant rhesus monkeys and guinea pigs. Using standard risk assessment methodology including hazard identification, exposure assessment, hazard characterization, and risk characterization, risk was calculated based on the new dose‐response information. To compare models, we looked at mortality rate per serving at predicted doses ranging from 10^?4 to 10¹² L. monocytogenes cfu. Based on a serving of 10⁶ L. monocytogenes cfu, the primate model predicts a death rate of 5.9 × 10^?1 compared to the FDA/USDA/CDC (fig. IV‐12)^{( 1 )} predicted rate of 1.3 × 10^?7. Based on the guinea pig and primate models, the mortality rate calculated by the FDA/USDA/CDC^{( 1 )} is underestimated for this susceptible population.     

Estimating Listeria monocytogenes Growth in Ready-to-Eat Chicken Salad Using a Challenge Test for Quantitative Microbial Risk Assessment

Currently, there is a growing preference for convenience food products, such as ready-to-eat (RTE) foods, associated with long refrigerated shelf-lives, not requiring a heat treatment prior to consumption. Because Listeria monocytogenes is able to grow at refrigeration temperatures, inconsistent temperatures during production, distribution, and at consumer's household may allow for the pathogen to thrive, reaching unsafe limits. L. monocytogenes is the causative agent of listeriosis, a rare but severe human illness, with high fatality rates, transmitted almost exclusively by food consumption. With the aim of assessing the quantitative microbial risk of L. monocytogenes in RTE chicken salads, a challenge test was performed. Salads were inoculated with a three-strain mixture of cold-adapted L. monocytogenes and stored at 4, 12, and 16 °C for eight days. Results revealed that the salad was able to support L. monocytogenes’ growth, even at refrigeration temperatures. The Baranyi primary model was fitted to microbiological data to estimate the pathogen's growth kinetic parameters. Temperature effect on the maximum specific growth rate (μ_max) was modeled using a square-root-type model. Storage temperature significantly influenced μ_max of L. monocytogenes (p < 0.05). These predicted growth models for L. monocytogenes were subsequently used to develop a quantitative microbial risk assessment, estimating a median number of 0.00008726 listeriosis cases per year linked to the consumption of these RTE salads. Sensitivity analysis considering different time–temperature scenarios indicated a very low median risk per portion (<−7 log), even if the assessed RTE chicken salad was kept in abuse storage conditions.     

Risk Assessment of Human Listeriosis from Semisoft Cheeses Made from Raw Sheep's Milk in Lazio and Tuscany (Italy)

Semisoft cheese made from raw sheep's milk is traditionally and economically important in southern Europe. However, raw milk cheese is also a known vehicle of human listeriosis and contamination of sheep cheese with Listeria monocytogenes has been reported. In the present study, we have developed and applied a quantitative risk assessment model, based on available evidence and challenge testing, to estimate risk of invasive listeriosis due to consumption of an artisanal sheep cheese made with raw milk collected from a single flock in central Italy. In the model, contamination of milk may originate from the farm environment or from mastitic animals, with potential growth of the pathogen in bulk milk and during cheese ripening. Based on the 48‐day challenge test of a local semisoft raw sheep's milk cheese we found limited growth only during the initial phase of ripening (24 hours) and no growth or limited decline during the following ripening period. In our simulation, in the baseline scenario, 2.2% of cheese servings are estimated to have at least 1 colony forming unit (CFU) per gram. Of these, 15.1% would be above the current E.U. limit of 100 CFU/g (5.2% would exceed 1,000 CFU/g). Risk of invasive listeriosis per random serving is estimated in the 10^?12 range (mean) for healthy adults, and in the 10^?10 range (mean) for vulnerable populations. When small flocks (10–36 animals) are combined with the presence of a sheep with undetected subclinical mastitis, risk of listeriosis increases and such flocks may represent a public health risk.     

Risk‐Based Approach for Microbiological Food Safety Management in the Dairy Industry: The Case of Listeria monocytogenes in Soft Cheese Made from Pasteurized Milk

According to Codex Alimentarius Commission recommendations, management options applied at the process production level should be based on good hygiene practices, HACCP system, and new risk management metrics such as the food safety objective. To follow this last recommendation, the use of quantitative microbiological risk assessment is an appealing approach to link new risk‐based metrics to management options that may be applied by food operators. Through a specific case study, Listeria monocytogenes in soft cheese made from pasteurized milk, the objective of the present article is to practically show how quantitative risk assessment could be used to direct potential intervention strategies at different food processing steps. Based on many assumptions, the model developed estimates the risk of listeriosis at the moment of consumption taking into account the entire manufacturing process and potential sources of contamination. From pasteurization to consumption, the amplification of a primo‐contamination event of the milk, the fresh cheese or the process environment is simulated, over time, space, and between products, accounting for the impact of management options, such as hygienic operations and sampling plans. A sensitivity analysis of the model will help orientating data to be collected prioritarily for the improvement and the validation of the model. What‐if scenarios were simulated and allowed for the identification of major parameters contributing to the risk of listeriosis and the optimization of preventive and corrective measures.     

QMRA for Drinking Water: 2. The Effect of Pathogen Clustering in Single‐Hit Dose‐Response Models

Spatial and/or temporal clustering of pathogens will invalidate the commonly used assumption of Poisson‐distributed pathogen counts (doses) in quantitative microbial risk assessment. In this work, the theoretically predicted effect of spatial clustering in conventional “single‐hit” dose‐response models is investigated by employing the stuttering Poisson distribution, a very general family of count distributions that naturally models pathogen clustering and contains the Poisson and negative binomial distributions as special cases. The analysis is facilitated by formulating the dose‐response models in terms of probability generating functions. It is shown formally that the theoretical single‐hit risk obtained with a stuttering Poisson distribution is lower than that obtained with a Poisson distribution, assuming identical mean doses. A similar result holds for mixed Poisson distributions. Numerical examples indicate that the theoretical single‐hit risk is fairly insensitive to moderate clustering, though the effect tends to be more pronounced for low mean doses. Furthermore, using Jensen's inequality, an upper bound on risk is derived that tends to better approximate the exact theoretical single‐hit risk for highly overdispersed dose distributions. The bound holds with any dose distribution (characterized by its mean and zero inflation index) and any conditional dose‐response model that is concave in the dose variable. Its application is exemplified with published data from Norovirus feeding trials, for which some of the administered doses were prepared from an inoculum of aggregated viruses. The potential implications of clustering for dose‐response assessment as well as practical risk characterization are discussed.     

Quantitative Risk Assessment of Vibrio parahaemolyticus in Finfish: A Model of Raw Horse Mackerel Consumption in Japan

The aim of this study was to evaluate the effects of implemented control measures to reduce illness induced by Vibrio parahaemolyticus (V. parahaemolyticus) in horse mackerel (Trachurus japonicus), seafood that is commonly consumed raw in Japan. On the basis of currently available experimental and survey data, we constructed a quantitative risk model of V. parahaemolyticus in horse mackerel from harvest to consumption. In particular, the following factors were evaluated: bacterial growth at all stages, effects of washing the fish body and storage water, and bacterial transfer from the fish surface, gills, and intestine to fillets during preparation. New parameters of the beta‐Poisson dose‐response model were determined from all human feeding trials, some of which have been used for risk assessment by the U.S. Food and Drug Administration (USFDA). The probability of illness caused by V. parahaemolyticus was estimated using both the USFDA dose‐response parameters and our parameters for each selected pathway of scenario alternatives: washing whole fish at landing, storage in contaminated water, high temperature during transportation, and washing fish during preparation. The last scenario (washing fish during preparation) was the most effective for reducing the risk of illness by about a factor of 10 compared to no washing at this stage. Risk of illness increased by 50% by exposure to increased temperature during transportation, according to our assumptions of duration and temperature. The other two scenarios did not significantly affect risk. The choice of dose‐response parameters was not critical for evaluation of control measures.     

Some Limitations of “Risk = Threat × Vulnerability × Consequence” for Risk Analysis of Terrorist Attacks

Several important risk analysis methods now used in setting priorities for protecting U.S. infrastructures against terrorist attacks are based on the formula: Risk=Threat×Vulnerability×Consequence. This article identifies potential limitations in such methods that can undermine their ability to guide resource allocations to effectively optimize risk reductions. After considering specific examples for the Risk Analysis and Management for Critical Asset Protection (RAMCAP?) framework used by the Department of Homeland Security, we address more fundamental limitations of the product formula. These include its failure to adjust for correlations among its components, nonadditivity of risks estimated using the formula, inability to use risk‐scoring results to optimally allocate defensive resources, and intrinsic subjectivity and ambiguity of Threat, Vulnerability, and Consequence numbers. Trying to directly assess probabilities for the actions of intelligent antagonists instead of modeling how they adaptively pursue their goals in light of available information and experience can produce ambiguous or mistaken risk estimates. Recent work demonstrates that two‐level (or few‐level) hierarchical optimization models can provide a useful alternative to Risk=Threat×Vulnerability×Consequence scoring rules, and also to probabilistic risk assessment (PRA) techniques that ignore rational planning and adaptation. In such two‐level optimization models, defender predicts attacker's best response to defender's own actions, and then chooses his or her own actions taking into account these best responses. Such models appear valuable as practical approaches to antiterrorism risk analysis.     

Development of an Interspecies Nested Dose‐Response Model for Mycobacterium avium subspecies paratuberculosis

Mycobacterium avium subspecies paratuberculosis (MAP) causes chronic inflammation of the intestines in humans, ruminants, and other species. It is the causative agent of Johne's disease in cattle, and has been implicated as the causative agent of Crohn's disease in humans. To date, no quantitative microbial risk assessment (QMRA) for MAP utilizing a dose‐response function exists. The objective of this study is to develop a nested dose‐response model for infection from oral exposure to MAP utilizing data from the peer‐reviewed literature. Four studies amenable to dose‐response modeling were identified in the literature search and optimized to the one‐parameter exponential or two‐parameter beta‐Poisson dose‐response models. A nesting analysis was performed on all permutations of the candidate data sets to determine the acceptability of pooling data sets across host species. Three of four data sets exhibited goodness of fit to at least one model. All three data sets exhibited good fit to the beta‐Poisson model, and one data set exhibited goodness of fit, and best fit, to the exponential model. Two data sets were successfully nested using the beta‐Poisson model with parameters α = 0.0978 and N₅₀ = 2.70 × 10² CFU. These data sets were derived from sheep and red deer host species, indicating successful interspecies nesting, and demonstrate the highly infective nature of MAP. The nested dose‐response model described should be used for future QMRA research regarding oral exposure to MAP.     

Evaluation of Inhaled Versus Deposited Dose Using the Exponential Dose‐Response Model for Inhalational Anthrax in Nonhuman Primate,Rabbit, and Guinea Pig

The application of the exponential model is extended by the inclusion of new nonhuman primate (NHP), rabbit, and guinea pig dose‐lethality data for inhalation anthrax. Because deposition is a critical step in the initiation of inhalation anthrax, inhaled doses may not provide the most accurate cross‐species comparison. For this reason, species‐specific deposition factors were derived to translate inhaled dose to deposited dose. Four NHP, three rabbit, and two guinea pig data sets were utilized. Results from species‐specific pooling analysis suggested all four NHP data sets could be pooled into a single NHP data set, which was also true for the rabbit and guinea pig data sets. The three species‐specific pooled data sets could not be combined into a single generic mammalian data set. For inhaled dose, NHPs were the most sensitive (relative lowest LD₅₀) species and rabbits the least. Improved inhaled LD₅₀s proposed for use in risk assessment are 50,600, 102,600, and 70,800 inhaled spores for NHP, rabbit, and guinea pig, respectively. Lung deposition factors were estimated for each species using published deposition data from Bacillus spore exposures, particle deposition studies, and computer modeling. Deposition was estimated at 22%, 9%, and 30% of the inhaled dose for NHP, rabbit, and guinea pig, respectively. When the inhaled dose was adjusted to reflect deposited dose, the rabbit animal model appears the most sensitive with the guinea pig the least sensitive species.     

Development of Dose‐Response Models to Predict the Relationship for Human Toxoplasma gondii Infection Associated with Meat Consumption

Toxoplasma gondii is a protozoan parasite that is responsible for approximately 24% of deaths attributed to foodborne pathogens in the United States. It is thought that a substantial portion of human T. gondii infections is acquired through the consumption of meats. The dose‐response relationship for human exposures to T. gondii‐infected meat is unknown because no human data are available. The goal of this study was to develop and validate dose‐response models based on animal studies, and to compute scaling factors so that animal‐derived models can predict T. gondii infection in humans. Relevant studies in literature were collected and appropriate studies were selected based on animal species, stage, genotype of T. gondii, and route of infection. Data were pooled and fitted to four sigmoidal‐shaped mathematical models, and model parameters were estimated using maximum likelihood estimation. Data from a mouse study were selected to develop the dose‐response relationship. Exponential and beta‐Poisson models, which predicted similar responses, were selected as reasonable dose‐response models based on their simplicity, biological plausibility, and goodness fit. A confidence interval of the parameter was determined by constructing 10,000 bootstrap samples. Scaling factors were computed by matching the predicted infection cases with the epidemiological data. Mouse‐derived models were validated against data for the dose‐infection relationship in rats. A human dose‐response model was developed as P (d) = 1–exp (–0.0015 × 0.005 × d) or P (d) = 1–(1 + d × 0.003 / 582.414)^?1.479. Both models predict the human response after consuming T. gondii‐infected meats, and provide an enhanced risk characterization in a quantitative microbial risk assessment model for this pathogen.     

Evaluating the Potential for a Helicobacter pylori Drinking Water Guideline

Helicobacter pylori is a microaerophilic, gram‐negative bacterium that is linked to adverse health effects including ulcers and gastrointestinal cancers. The goal of this analysis is to develop the necessary inputs for a quantitative microbial risk assessment (QMRA) needed to develop a potential guideline for drinking water at the point of ingestion (e.g., a maximum contaminant level, or MCL) that would be protective of human health to an acceptable level of risk while considering sources of uncertainty. Using infection and gastric cancer as two discrete endpoints, and calculating dose‐response relationships from experimental data on humans and monkeys, we perform both a forward and reverse risk assessment to determine the risk from current reported surface water concentrations of H. pylori and an acceptable concentration of H. pylori at the point of ingestion. This approach represents a synthesis of available information on human exposure to H. pylori via drinking water. A lifetime risk of cancer model suggests that a MCL be set at <1 organism/L given a 5‐log removal treatment because we cannot exclude the possibility that current levels of H. pylori in environmental source waters pose a potential public health risk. Research gaps include pathogen occurrence in source and finished water, treatment removal rates, and determination of H. pylori risks from other water sources such as groundwater and recreational water.     

Classification of Listeria monocytogenes Persistence in Retail Delicatessen Environments Using Expert Elicitation and Machine Learning

Increasing evidence suggests that persistence of Listeria monocytogenes in food processing plants has been the underlying cause of a number of human listeriosis outbreaks. This study extracts criteria used by food safety experts in determining bacterial persistence in the environment, using retail delicatessen operations as a model. Using the Delphi method, we conducted an expert elicitation with 10 food safety experts from academia, industry, and government to classify L. monocytogenes persistence based on environmental sampling results collected over six months for 30 retail delicatessen stores. The results were modeled using variations of random forest, support vector machine, logistic regression, and linear regression; variable importance values of random forest and support vector machine models were consolidated to rank important variables in the experts’ classifications. The duration of subtype isolation ranked most important across all expert categories. Sampling site category also ranked high in importance and validation errors doubled when this covariate was removed. Support vector machine and random forest models successfully classified the data with average validation errors of 3.1% and 2.2% (n = 144), respectively. Our findings indicate that (i) the frequency of isolations over time and sampling site information are critical factors for experts determining subtype persistence, (ii) food safety experts from different sectors may not use the same criteria in determining persistence, and (iii) machine learning models have potential for future use in environmental surveillance and risk management programs. Future work is necessary to validate the accuracy of expert and machine classification against biological measurement of L. monocytogenes persistence.     

Animal and Human Dose‐Response Models for Brucella Species

Human Brucellosis is one of the most common zoonotic diseases worldwide. Disease transmission often occurs through the handling of domestic livestock, as well as ingestion of unpasteurized milk and cheese, but can have enhanced infectivity if aerosolized. Because there is no human vaccine available, rising concerns about the threat of Brucellosis to human health and its inclusion in the Center for Disease Control's Category B Bioterrorism/Select Agent List make a better understanding of the dose‐response relationship of this microbe necessary. Through an extensive peer‐reviewed literature search, candidate dose‐response data were appraised so as to surpass certain standards for quality. The statistical programming language, “R,” was used to compute the maximum likelihood estimation to fit two models, the exponential and the approximate beta‐Poisson (widely used for quantitative risk assessment) to dose‐response data. Dose‐response models were generated for prevalent species of Brucella: Br. suis, Br. melitensis, and Br. abortus. Dose‐response models were created for aerosolized Br. suis exposure to guinea pigs from pooled studies. A parallel model for guinea pigs inoculated through both aerosol and subcutaneous routes with Br. melitensis showed that the median infectious dose corresponded to a 30 colony‐forming units (CFU) dose of Br. suis, much less than the N₅₀ dose of about 94 CFU for Br. melitensis organisms. When Br. melitensis was tested subcutaneously on mice, the N₅₀ dose was higher, 1,840 CFU. A dose‐response model was constructed from pooled data for mice, rhesus macaques, and humans inoculated through three routes (subcutaneously/aerosol/intradermally) with Br. melitensis.     

Outbreak-Based Giardia Dose–Response Model Using Bayesian Hierarchical Markov Chain Monte Carlo Analysis

Giardia is a zoonotic gastrointestinal parasite responsible for a substantial global public health burden, and quantitative microbial risk assessment (QMRA) is often used to forecast and manage this burden. QMRA requires dose–response models to extrapolate available dose–response data, but the existing model for Giardia ignores valuable dose–response information, particularly data from several well-documented waterborne outbreaks of giardiasis. The current study updates Giardia dose–response modeling by synthesizing all available data from outbreaks and experimental studies using a Bayesian random effects dose–response model. For outbreaks, mean doses (D) and the degree of spatial and temporal aggregation among cysts were estimated using exposure assessment implemented via two-dimensional Monte Carlo simulation, while potential overreporting of outbreak cases was handled using published overreporting factors and censored binomial regression. Parameter estimation was by Markov chain Monte Carlo simulation and indicated that a typical exponential dose–response parameter for Giardia is r = 1.6 × 10⁻² [3.7 × 10⁻³, 6.2 × 10⁻²] (posterior median [95% credible interval]), while a typical morbidity ratio is m = 3.8 × 10⁻¹ [2.3 × 10⁻¹, 5.5 × 10⁻¹]. Corresponding (logistic-scale) variance components were σ_r = 5.2 × 10⁻¹ [1.1 × 10⁻¹, 9.6 × 10⁻¹] and σ_m = 9.3 × 10⁻¹ [7.0 × 10⁻², 2.8 × 10⁰], indicating substantial variation in the Giardia dose–response relationship. Compared to the existing Giardia dose–response model, the current study provides more representative estimation of uncertainty in r and novel quantification of its natural variability. Several options for incorporating variability in r (and m) into QMRA predictions are discussed, including incorporation via Monte Carlo simulation as well as evaluation of the current study's model using the approximate beta-Poisson.     

A gradient Markov chain Monte Carlo algorithm for computing multivariate maximum likelihood estimates and posterior distributions: mixture dose-response assessment

Multivariate probability distributions, such as may be used for mixture dose‐response assessment, are typically highly parameterized and difficult to fit to available data. However, such distributions may be useful in analyzing the large electronic data sets becoming available, such as dose‐response biomarker and genetic information. In this article, a new two‐stage computational approach is introduced for estimating multivariate distributions and addressing parameter uncertainty. The proposed first stage comprises a gradient Markov chain Monte Carlo (GMCMC) technique to find Bayesian posterior mode estimates (PMEs) of parameters, equivalent to maximum likelihood estimates (MLEs) in the absence of subjective information. In the second stage, these estimates are used to initialize a Markov chain Monte Carlo (MCMC) simulation, replacing the conventional burn‐in period to allow convergent simulation of the full joint Bayesian posterior distribution and the corresponding unconditional multivariate distribution (not conditional on uncertain parameter values). When the distribution of parameter uncertainty is such a Bayesian posterior, the unconditional distribution is termed predictive. The method is demonstrated by finding conditional and unconditional versions of the recently proposed emergent dose‐response function (DRF). Results are shown for the five‐parameter common‐mode and seven‐parameter dissimilar‐mode models, based on published data for eight benzene–toluene dose pairs. The common mode conditional DRF is obtained with a 21‐fold reduction in data requirement versus MCMC. Example common‐mode unconditional DRFs are then found using synthetic data, showing a 71% reduction in required data. The approach is further demonstrated for a PCB 126‐PCB 153 mixture. Applicability is analyzed and discussed. Matlab^® computer programs are provided.     

Impact of Acquired Immunity and Dose‐Dependent Probability of Illness on Quantitative Microbial Risk Assessment

Dose‐response models in microbial risk assessment consider two steps in the process ultimately leading to illness: from exposure to (asymptomatic) infection, and from infection to (symptomatic) illness. Most data and theoretical approaches are available for the exposure‐infection step; the infection‐illness step has received less attention. Furthermore, current microbial risk assessment models do not account for acquired immunity. These limitations may lead to biased risk estimates. We consider effects of both dose dependency of the conditional probability of illness given infection, and acquired immunity to risk estimates, and demonstrate their effects in a case study on exposure to Campylobacter jejuni. To account for acquired immunity in risk estimates, an inflation factor is proposed. The inflation factor depends on the relative rates of loss of protection over exposure. The conditional probability of illness given infection is based on a previously published model, accounting for the within‐host dynamics of illness. We find that at low (average) doses, the infection‐illness model has the greatest impact on risk estimates, whereas at higher (average) doses and/or increased exposure frequencies, the acquired immunity model has the greatest impact. The proposed models are strongly nonlinear, and reducing exposure is not expected to lead to a proportional decrease in risk and, under certain conditions, may even lead to an increase in risk. The impact of different dose‐response models on risk estimates is particularly pronounced when introducing heterogeneity in the population exposure distribution.     

Risks of Allergic Contact Dermatitis Elicited by Nickel,Chromium, and Organic Sensitizers: Quantitative Models Based on Clinical Patch Test Data

Risks of allergic contact dermatitis (ACD) from consumer products intended for extended (nonpiercing) dermal contact are regulated by E.U. Directive EN 1811 that limits released Ni to a weekly equivalent dermal load of ≤0.5 μg/cm². Similar approaches for thousands of known organic sensitizers are hampered by inability to quantify respective ACD‐elicitation risk levels. To help address this gap, normalized values of cumulative risk for eliciting a positive (“≥+”) clinical patch test response reported in 12 studies for a total of n = 625 Ni‐sensitized patients were modeled in relation to observed ACD‐eliciting Ni loads, yielding an approximate lognormal (LN) distribution with a geometric mean and standard deviation of GM_Ni = 15 μg/cm² and GSD_Ni = 8.0, respectively. Such data for five sensitizers (including formaldehyde and 2‐hydroxyethyl methacrylate) were also ∼LN distributed, but with a common GSD value equal to GSD_Ni and with heterogeneous sensitizer‐specific GM values each defining a respective ACD‐eliciting potency GM_Ni/GM relative to Ni. Such potencies were also estimated for nine (meth)acrylates by applying this general LN ACD‐elicitation risk model to respective sets of fewer data. ACD‐elicitation risk patterns observed for Cr(VI) (n = 417) and Cr(III) (n = 78) were fit to mixed‐LN models in which ∼30% and ∼40% of the most sensitive responders, respectively, were estimated to exhibit a LN response also governed by GSD_Ni. The observed common LN‐response shape parameter GSD_Ni may reflect a common underlying ACD mechanism and suggests a common interim approach to quantitative ACD‐elicitation risk assessment based on available clinical data.     

Modeling Rabbit Responses to Single and Multiple Aerosol Exposures of Bacillus anthracis Spores

Survival models are developed to predict response and time‐to‐response for mortality in rabbits following exposures to single or multiple aerosol doses of Bacillus anthracis spores. Hazard function models were developed for a multiple‐dose data set to predict the probability of death through specifying functions of dose response and the time between exposure and the time‐to‐death (TTD). Among the models developed, the best‐fitting survival model (baseline model) is an exponential dose–response model with a Weibull TTD distribution. Alternative models assessed use different underlying dose–response functions and use the assumption that, in a multiple‐dose scenario, earlier doses affect the hazard functions of each subsequent dose. In addition, published mechanistic models are analyzed and compared with models developed in this article. None of the alternative models that were assessed provided a statistically significant improvement in fit over the baseline model. The general approach utilizes simple empirical data analysis to develop parsimonious models with limited reliance on mechanistic assumptions. The baseline model predicts TTDs consistent with reported results from three independent high‐dose rabbit data sets. More accurate survival models depend upon future development of dose–response data sets specifically designed to assess potential multiple‐dose effects on response and time‐to‐response. The process used in this article to develop the best‐fitting survival model for exposure of rabbits to multiple aerosol doses of B. anthracis spores should have broad applicability to other host–pathogen systems and dosing schedules because the empirical modeling approach is based upon pathogen‐specific empirically‐derived parameters.