The design of a matrix linking work situations to chemical health risk at the workplace.

In France, laws require each company to draw up an inventory of the risks that may threaten employees' health in order to prioritize the preventive actions to be implemented. Focusing on chemical risk, databases on hazards or exposures are widely available but they lack information regarding chemical risks resulting from combining the hazards of chemicals with their conditions of use, thus generating exposures. Our objective is to build a matrix of French work situations associated with their chemical risk. Eighty-eight work situations were collected from reports written by professionals from the French public health insurance service. Each work situation is defined by descriptive parameters of the task, the exposure, and the hazard. According to an expert elicitation method (Delphi, n = 21 experts), each work situation was assessed and a chemical risk score defined, taking into account all the descriptive exposure and hazard parameters. Chemical risk scores were expressed as a range of values from 0 to 100, with the size of the range chosen by the experts themselves according to their uncertainty. The experts' assessments were merged to assign one risk score for each work situation, variability, and confidence. The results showed that 50% of the work situations had a risk score between 40 and 60. The average variability and confidence were around 15% and 82%, respectively. This work situation matrix constructed from French data can be used by occupational safety and health managers that have similar work situations in their company (Western European industrial sector). In this context, it may be useful to easily determine the level of risks for similar tasks and prioritize those that are most risky. Moreover, it could be used to compare and define the differences between a risk assessment performed by "expertise" and another defined by a software.

TOXsIgN: a cross-species repository for toxicogenomic signatures.

Motivation: At the same time that toxicologists express increasing concern about reproducibility in this field, the development of dedicated databases has already smoothed the path toward improving the storage and exchange of raw toxicogenomic data. Nevertheless, none provides access to analyzed and interpreted data as originally reported in scientific publications. Given the increasing demand for access to this information, we developed TOXsIgN, a repository for TOXicogenomic sIgNatures. Results: The TOXsIgN repository provides a flexible environment that facilitates online submission, storage and retrieval of toxicogenomic signatures by the scientific community. It currently hosts 754 projects that describe more than 450 distinct chemicals and their 8491 associated signatures. It also provides users with a working environment containing a powerful search engine as well as bioinformatics/biostatistics modules that enable signature comparisons or enrichment analyses. Availability and implementation: The TOXsIgN repository is freely accessible at http://toxsign.genouest.org. Website implemented in Python, JavaScript and MongoDB, with all major browsers supported. Supplementary information: Supplementary data are available at Bioinformatics online.

Aggregating exposures & cumulating risk for semivolatile organic compounds: A review.

Increasingly, health risk assessment is addressing multiple pathway exposures to multiple contaminants. We reviewed aggregated exposure and cumulative risk approaches for contemporary and ubiquitous semivolatile organic compounds (SVOC). We identified 22 studies aggregating exposure pathways, and 31 cumulating risk. Exposure aggregation is based on the addition of pathway-specific doses, using kinetic modeling where it exists, and classic external dose equations otherwise. In most cases, exposure is dominated by a single route or source of exposure - mainly the oral pathway - via dietary or non-dietary exposure. Preferential routes and sources of exposure are influenced by SVOC physical-chemical properties such as vapor pressure. The cumulative risk approach for contaminants is based on dose addition. Simple sum of hazard quotient (Hazard Index: HI) is the most commonly used cumulative risk assessment approach, while Relative Potency Factor (RPF) appeared to the best suited - although this calls for a level of toxicological information that limits the number of compounds that can be studied simultaneously. Where both were performed, moving from HI to more refined approach produced similar results. In conclusion, both approaches - exposure aggregation and cumulative risk - rely on simple assumptions. Nevertheless, they allow uncertainty to be reduced, in comparison with source-by-source or chemical-by-chemical approaches.

Prenatal exposure to persistent organic pollutants and organophosphate pesticides, and markers of glucose metabolism at birth.

BACKGROUND: Experimental evidence suggests that developmental exposure to persistent organic pollutants (POP) and to some non persistent pesticides may disrupt metabolic regulation of glucose metabolism and insulin secretion, and thereby contribute to the current epidemic of obesity and metabolic disorders. Quasi-experimental situations of undernutrition in utero have provided some information. However, the evidence in humans concerning the role of the prenatal environment in these disorders is contradictory, and little is known about long-term outcomes, such as type 2 diabetes, of prenatal exposure. OBJECTIVES: Our aim was to evaluate the effects of prenatal exposure to POP and organophosphate pesticides on fetal markers of glucose metabolism in a sample of newborns from the Pelagie mother-child cohort in Brittany (France). METHODS: Dialkylphosphate (DAP) metabolites of organophosphate pesticides were measured in maternal urine collected at the beginning of pregnancy. Cord blood was assayed for polychlorinated biphenyl congener 153 (PCB153), p,p'-dichlorodiphenyl dichloroethene (DDE) and other POP. Insulin and adiponectin were determined in cord blood serum (n=268). RESULTS: A decrease in adiponectin and insulin levels was observed with increasing levels of DDE, but only in girls and not boys. Adiponectin levels were not related to the concentrations of other POP or DAP metabolites. Decreasing insulin levels were observed with increasing PCB153 concentrations. Insulin levels increased with DAP urinary levels. Additional adjustment for BMI z-score at birth modified some of these relations. CONCLUSIONS: Our observations bring support for a potential role of organophosphate pesticides and POP in alterations to glucose metabolism observable at birth.

Potential input from metabolomics for exploring and understanding the links between environment and health.

Humans may be exposed via their environment to multiple chemicals as a consequence of human activities and use of synthetic products. Little knowledge is routinely generated on the hazards of these chemical mixtures. The metabolomic approach is widely used to identify metabolic pathways modified by diseases, drugs, or exposures to toxicants. This review, based on the state of the art of the current applications of metabolomics in environmental health, attempts to determine whether metabolomics might constitute an original approach to the study of associations between multiple, low-dose environmental exposures in humans. Studying the biochemical consequences of complex environmental exposures is a challenge demanding the development of careful experimental and epidemiological designs, in order to take into account possible confounders associated with the high level of interindividual variability induced by different lifestyles. The choices of populations studied, sampling and storage procedures, statistical tools used, and system biology need to be considered. Suggestions for improved experimental and epidemiological designs are described. Evidence indicates that metabolomics may be a powerful tool in environmental health in the identification of both complex exposure biomarkers directly in human populations and modified metabolic pathways, in an attempt to improve understanding the underlying environmental causes of diseases. Nevertheless, the validity of biomarkers and relevancy of animal-to-human extrapolation remain key challenges that need to be properly explored.

Semivolatile organic compounds in indoor air and settled dust in 30 French dwellings.

Semivolatile organic compounds (SVOCs) are ubiquitous contaminants in indoor environments, emanating from different sources and partitioning among several compartments, including the gas phase, airborne particles, and settled dust. Nevertheless, simultaneous measurements in the three compartments are rarely reported. In this study, we investigated indoor concentrations of a wide range of SVOCs in 30 French dwellings. In settled dust, 40 out of 57 target compounds were detected. The highest median concentrations were measured for phthalates and to a lesser extent for bisphenol A, synthetic musks, some pesticides, and PAHs. Di(2-ethylhexyl)phthalate (DEHP) and diisononyl phthalate (DINP) were the most abundant compounds. A total of 34 target compounds were detected both in the gas phase and airborne particles. The highest concentrations were measured for diisobutyl phthalate (DiBP), diethyl phthalate (DEP), dibutyl phthalate (DBP), and synthetic musks in the gas phase and for DEHP, DiBP, DBP, and DINP in the airborne particles. This is the first study on the indoor concentrations of a wide range of SVOCs in settled dust, gas phase, and airborne particles collected simultaneously in each dwelling.

Untargeted profiling of pesticide metabolites by LC-HRMS: an exposomics tool for human exposure evaluation.

Human exposure to xenobiotics is usually estimated by indirect methods. Biological monitoring has emerged during the last decade to improve assessment of exposure. However, biomonitoring is still an analytical challenge, because the amounts of sample available are often very small yet analysis must be as thorough and sensitive as possible. The purpose of this work was to develop an untargeted "exposomics" approach by using ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS), which was applied to the characterization of pesticide metabolites in urine from pregnant women from a French epidemiological cohort. An upgradable list of pesticides commonly used on different crops, with their metabolites (more than 400 substances) was produced. Raw MS data were then processed to extract signals from these substances. Metabolites were identified by tandem mass spectrometry; putative identifications were validated by comparison with standards and metabolites generated by experiments on animals. Finally, signals of identified compounds were statistically analyzed by use of multivariate methods. This enabled discrimination of exposure groups, defined by indirect methods, on the basis of four metabolites from two fungicides (azoxystrobin, fenpropimorph) used in cereal production. This original approach applied to pesticide exposure can be extended to a variety of contaminant families for upstream evaluation of exposure from food and the environment.

An exposure-based framework for grouping pollutants for a cumulative risk assessment approach: case study of indoor semi-volatile organic compounds.

Humans are exposed to a large number of contaminants, many of which may have similar health effects. This paper presents a framework for identifying pollutants to be included in a cumulative risk assessment approach. To account for the possibility of simultaneous exposure to chemicals with common toxic modes of action, the first step of the traditional risk assessment process, i.e. hazard identification, is structured in three sub-steps: (1a) Identification of pollutants people are exposed to, (1b) identification of effects and mechanisms of action of these pollutants, (1c) grouping of pollutants according to similarity of their mechanism of action and health effects. Based on this exposure-based grouping we can derive "multi-pollutant" toxicity reference values, in the "dose-response assessment" step. The approach proposed in this work is original in that it is based on real exposures instead of a limited number of pollutants from a unique chemical family, as traditionally performed. This framework is illustrated by the case study of semi-volatile organic compounds in French dwellings, providing insights into practical considerations regarding the accuracy of the available toxicological information. This case study illustrates the value of the exposure-based approach as opposed to the traditional cumulative framework, in which chemicals with similar health effects were not always included in the same chemical class.

Prevalence of occupational co-exposure to biomechanical factors and neurotoxic chemicals in French workers.

OBJECTIVES: Little is known about occupational co-exposure. The objective was to assess the prevalence of exposure and co-exposure to biomechanical factors and neurotoxic chemicals in French workers in 2017. METHODS: Data from the French representative survey SUMER 2017 (SUrveillance Médicale des Expositions aux Risques professionnels) were analyzed. A total of 25 118 workers were included. Exposure to 4 biomechanical factors (manual handling of loads, forceful joint exertion, repetitive movements, and hand-arm transmitted vibrations) and 18 neurotoxic chemicals (n-hexane, perchloroethylene, trichloroethylene, etc.) were assessed using a questionnaire during face-to-face interviews with occupational physicians. RESULTS: Among men, 22.9% were exposed to at least one biomechanical factor and 10.2% were exposed to at least one neurotoxic chemical, mainly single exposures. Among women, 10.8% were exposed to at least one biomechanical factor and 3.1% were exposed to at least one neurotoxic chemical, also mainly single exposures. Occupational co-exposure to biomechanical factors and neurotoxic chemicals was observed among 4.8% of men and 0.7% of women. Workers under 30 yr old, blue-collar workers and those working in small companies were more co-exposed than other workers. In men, the prevalence of co-exposure was higher in the construction sector compared to other economic activities. DISCUSSION: This study stresses the importance of considering multiple occupational exposures while the current prevention measures are designed to focus on preventing occupational factors individually.

Characterization of organic contaminants in hair for biomonitoring purposes.

Biological monitoring is one way to assess human exposure to contaminants. Blood and urine are often used as biological matrices, but hair is an innovative and effective tool for quantifying more biomarkers over a wider exposure window. In order to improve the use of hair in exposure assessment, this article identifies relevant compounds in the literature to investigate hair contamination. Statistical analysis was performed to correlate the physical-chemical properties of the relevant compounds and their concentration levels in hair. Phthalates, pyrethroids and organophosphate flame retardants were chosen for further study of the interpretation of hair measurements for exposure assessment. No significant correlation was found between the average concentration levels in the literature and the physical-chemical properties of the selected compounds. This work also explores the properties of hair and the analytical process that may impact the quantification of organic contaminants in hair. The sample preparation method (sampling, storage, washing) were also studied and adaptations were suggested to improve the existing methods.

Biocide and other semi-volatile organic compound concentrations in settled indoor dust of CRESPI daycare centers and implication for public health.

This study investigates the presence of biocides and other semi-volatile organic compounds (SVOCs) in cleaning products used in daycare centers and health impact through ingestion of settled dust by young children. In Paris metropolitan area, 106 daycares area were investigated between 2019-2022. Fifteen substances were analyzed in settled indoor dust by gas chromatography-tandem mass spectrometry. Detection rates and concentrations ranged from 5 to 100%, and

A control banding method for chemical risk assessment in occupational settings in France.

Background: This study describes a method whose aim is to help companies assess the chemical occupational risks related to labeled products and industrial chemical emissions. The method is intended to be used by industrial hygienists at the scale of one company. Both inhalation and cutaneous exposure routes are taken into account. Methods: The method relies on a control-banding scheme. A work situation is described by exposure parameters such as the process or the local exhaust ventilation and by the hazard of the product. Each possible value of the parameters is associated with a "band," which is associated with an integer value. The multiplication of these values results in a score, which represents a priority for intervention. The higher the score, the more the situation warrants investigation for implementing prevention measures, such as chemical substitution and the addition of local exhaust ventilation. To simplify communication, the priority is associated with a colored priority band: red for "very high priority," orange for "high priority," and green for "moderate priority." The priority bands are computed for all work situations performed in a company. Results: An example of the use of this method is described in a French façade insulation company. Conclusion: A tool named Seirich was developed to implement this method and promote good practices for helping industrial hygienists in the prioritization of interventions for reducing chemical risk in France.

Determination of glyphosate and AMPA in indoor settled dust by hydrophilic interaction liquid chromatography with tandem mass spectrometry and implications for human exposure.

The widespread application of glyphosate leads to significant contamination of outdoor environmental compartments, notably air and soil, which can contaminate indoor air and dust. This study assessed the contamination of indoor household dust for the first time in France and potential exposure to glyphosate through the inadvertent ingestion of dust. A specific and new analytical method was developed using HILIC MS/MS (hydrophilic interaction liquid chromatography with tandem mass spectrometry) to measure polar pesticides, such as glyphosate, aminomethylphosphonic acid, and glufosinate, in indoor dust, with a low quantification limit (25 ng/g). The dust from vacuum cleaner bags of 60 rural and urban households (Brittany, France) was analyzed. All samples contained glyphosate (median 1675 ng/g for rural dwellings (n = 29), 457 ng/g for urban dwellings (n = 31)), more than 90 % contained aminomethylphosphonic acid, and none contained glufosinate. Concentrations were influenced by the rural or urban setting, the proximity of crops, and the use of weed killers on driveways or lawns. Glyphosate exposure via indoor dust ingestion was < 1 % of both acceptable daily intake and dietary intake. However, the high quantification limit of the glyphosate concentration in the food analysis method probably leads to overestimation of the dose from food.

Exposure during pregnancy to glycol ethers and chlorinated solvents and the risk of congenital malformations.

BACKGROUND: Exposure to solvents during pregnancy has long been suspected of increasing the risk of congenital malformations, but the lack of prospective assessment of specific solvent exposures has prevented definitive conclusions. METHODS: In a cohort of 3421 pregnant women in Brittany (2002-2006), occupational solvent exposure was assessed from self-report during pregnancy and from a job-exposure matrix. Congenital malformations were diagnosed among live births, stillbirths, and medical pregnancy terminations. In a nested case-control sample, urinary concentrations of 10 metabolites of glycol ethers and chlorinated solvents were measured in maternal samples collected during early pregnancy (n = 79 cases, 580 controls). RESULTS: Dose-response trends linked occupational solvent exposure (both self-reported and based on a job-exposure matrix) to the risk of major congenital malformations--especially oral clefts, urinary tract malformations, and male genital malformations. Detection of some glycol ether metabolites and trichloroacetic acid in urine was associated with increased risks of oral clefts and of urinary tract and limb defects. CONCLUSIONS: This prospective study, using three independent methods of exposure assessment, suggests several specific associations between solvent exposure during early pregnancy and congenital malformations. Results based on urinary biomarkers, although limited by small numbers, identify work situations that require further investigation.

Urinary biomarkers of exposure to glycol ethers and chlorinated solvents during pregnancy: determinants of exposure and comparison with indirect methods of exposure assessment.

OBJECTIVES: To describe urine levels of metabolites of glycol ethers and chlorinated solvents in a sample of pregnant women from the general population, to study their occupational and non-occupational determinants and to compare them with the results of indirect assessment methods of solvent exposure. METHODS: A sample of 451 pregnant women was randomly selected from a general population cohort. At inclusion, the women in this sample completed a self-administered questionnaire about their social and medical characteristics, occupation and exposure to different products at work and in non-occupational activities. Occupational exposure to solvents was assessed from the woman's self-report and from a job-exposure matrix. Eight alkoxycarboxylic acids and trichloroacetic acid and trichloroethanol were measured with chromatography in urine samples collected at inclusion. Associations between metabolite levels and job titles, exposure to products used at work, and solvent exposure were studied. RESULTS: The different glycol ether metabolites were detected in 5.3%-96.4% of the urine samples, trichloroacetic acid in 6.4% and trichloroethanol in 5.5%. Nurses had butoxyacetic acid and phenoxyacetic acid in their urine most often, whereas methoxyethoxyacetic acid was the most frequent among nursing aides. Among cleaners, ethoxyacetic acid and ethoxyethoxyacetic acid were the most frequent. The occupation of hairdresser was associated with urinary excretion of ethoxyacetic acid, ethoxyethoxyacetic acid, butoxyacetic acid and phenoxyacetic acid. Among the women classified as exposed to solvents, the agents identified most often were ethoxyacetic acid, ethoxy-ethoxyacetic acid, butoxyacetic acid, phenoxyacetic acid, trichloroacetic acid and trichloroethanol. Ethoxyethoxyacetic acid was the only metabolite associated with non-occupational exposure. CONCLUSIONS: Metabolites of glycol ethers and chlorinated solvents were present at low levels in the urine of pregnant women. Most metabolites were associated with occupational exposure.

Analytical strategies to profile the internal chemical exposome and the metabolome of human placenta.

As a non-invasive biological matrix, the placenta offers great and novel opportunities to monitor fetal exposure to exogenous chemicals and their biotransformation products (the internal chemical exposome), as well as the biological responses associated, in large-scale epidemiological studies. However, it is first crucial to ensure that analytical methods based on high-resolution mass spectrometry (HRMS) can detect the low abundant components of the internal chemical exposome present in these complex biological matrices. In this study, we aimed to develop a robust analytical method (extraction and sample preparation) sensitive enough to profile the internal chemical exposome and the metabolome of placenta using high-resolution mass spectrometry (HRMS) for future application in mother child cohorts. Several extraction solvents (methanol, methanol/H2O (50/50 v/v), methyl tert-butyl ether/methanol/H2O) were tested and their ability to extract components of the internal exposome and metabolome were compared. Then, sample preparation methods commonly used for metabolomics application (methanolic protein precipitation) were compared with solid phase extraction (SPE), protein and phospholipid removal plates (PPRP) and combination of SPE and PPRP. The methods were compared and validated using qualitative (i.e., numbers of features and chemical classes ID), quantitative parameters adopted from targeted multi-residue analysis (recovery experiments, repeatability and matrix effect) as well as the ability of these methods to be implemented for high-throughput applications. The analytical repeatability of the two most effective methods (methanolic extraction followed by either protein precipitation or PPRP) were tested at the batch level to determine the best concentration factors to be used for improving detection of components of the internal chemical exposome and metabolome without impacting on the analytical response. Finally, these two methods based on protein precipitation and PPRP were tested on 40 placenta samples from the French PELAGIE birth cohort, and annotation was performed on the related datasets to compare the respective impacts of PPT and PPRP. A wide range of exogenous (e.g., biocides, pharmaceuticals, personal care products) and endogenous chemicals (steroids, prostanoids, lipids, carnitins) could be detected and annotated (some of them for the first time in placenta). We show that both methods are complementary but that PPRP allows the injection of more concentrated extracts without impacting the LC repeatability and therefore improve the detection (presence and signal area fold change) of many exogenous and endogenous chemicals.

Characterization of multiple pesticide exposure in pregnant women in Brittany, France.

BACKGROUND: France is one of the biggest users of pesticides in Europe and exposure to pesticides is a current concern, especially when it occurs early in life. OBJECTIVE: The aim of this study was to assess the exposure of pregnant women in Brittany (western France) with high pesticide use. METHODS: The pesticides were selected according to agricultural practices. Forty pesticides or metabolites were measured in urine samples collected in 2004 from 296 pregnant women in Brittany. The samples were analyzed by ultra-high performance liquid chromatography (UHPLC) coupled to high resolution mass spectrometry (HRMS) after a solid phase extraction (SPE) step. RESULTS: Twenty seven pesticides were detected: the most frequently detected were the metabolites of organophosphate and pyrethroid insecticides (>89%) and several herbicides (phenoxypropionic acid derivatives and fluazifop >60%). Organophosphate and pyrethroid metabolites were also quantified in highest levels with maximum values of 590 µg/l for dimethylphosphate and 5.4 µg/l for 3- phenoxybenzoic acid. For the other parent compounds, such as prochloraz, bromoxynil and procymidone, they were also detected in 10-29% of the samples. SIGNIFICANCE: Our results are consistent with pesticide use at the time of collection. The median concentrations of organophosphorus and pyrethroids were of the same order of magnitude as those reported in other countries. Herbicides and fungicides (fluazifop-p-butyl, bromoxynil, and prochloraz) were measured for the first time in this biomonitoring study, showing the usefulness of measuring widely used pesticides locally to improve knowledge of exposure. IMPACT: The objective of this study is to assess the exposure of pregnant women in a region of Europe with high pesticide use.

[Occupational exposome: An organisational model]. / Un modèle organisationnel de l'exposome professionnel.

This article describes the concept of occupational exposome in highlighting the value of the concept in understanding the complexity of workplace exposures and their determinants. An organizational approach to the occupational exposome is proposed. The organizational approach is intended, from an interdisciplinary perspective, to broaden the levels of analysis of the exposures (whether they are) of the individual to the work situation (individual or collective), the work situation in the workshop or in the service, the company and the socio-economic environment of the company, the socio-economic environment of the company to the Society as a whole. The organizational approach of the occupational exposome helps to broaden the spectrum of health risk assessment and to promote a comprehensive and integrated approach to the prevention of arduousness at work and occupational wear and tear.

Title: Un modèle organisationnel de l'exposome professionnel. Abstract: Dans cette revue, nous décrivons le concept d'exposome professionnel, en soulignant son intérêt pour appréhender la complexité des expositions en milieu de travail et saisir l'ensemble de leurs déterminants. Une approche organisationnelle de cet exposome est par ailleurs proposée. Elle vise, en lui donnant une perspective interdisciplinaire, à élargir les niveaux d'analyse des expositions, quelles qu'elles soient, de l'individu à la situation de travail, individuelle ou collective, de la situation de travail à l'atelier ou au service dans l'entreprise1 et son environnement socio-économique, et, enfin, de l'environnement socio-économique de l'entreprise à l'ensemble de la Société. Cette approche organisationnelle de l'exposome professionnel contribue également à élargir le spectre de l'évaluation des risques sanitaires et à promouvoir une approche globale et intégrée de la prévention de la pénibilité au travail et de l'usure professionnelle.

Proposal for a neurotoxic classification for chemicals at work.

Many neurotoxic chemicals are used in the workplace but there is currently no database dedicated to neurotoxicity. We aimed to develop a classification method for neurotoxicity based on a weight-of-evidence approach, similar to the IARC classification for carcinogenicity. Human and animal lines of evidence were collected from recent toxicological profiles and a literature search and were combined into six groups from neurotoxic to potentially not neurotoxic. The method was tested on 26 chemicals, mixtures or group of products used in the workplace in France: 31% were considered neurotoxic, 31% probably and 11% possibly neurotoxic, and 27% not classifiable because of insufficient data. This operational method suggests that many chemicals used in the workplace are neurotoxic and that questionnaires used to collect data on occupational chemical exposure should propose items with more targeted compounds that have common chemical or toxic properties to improve risk assessment.

Derivation of a toxicity reference value for nitrogen trichloride as a disinfection by-product.

Nitrogen trichloride is a highly volatile chlorination disinfection by-product, very commonly found in the air of indoor swimming pools. The aim of this work is to characterize the hazard associated with it and to determine the concentration at which health effects appear, for application in health risk assessments for users of indoor swimming pools. Hazard identification was based on a literature survey and analysis of animal and human studies, with special attention paid to their methodological quality and to reports of a dose-response relationship. A toxicity reference value was derived for respiratory effects, based on human data from both general and occupational data. We selected a lowest-observed-adverse-effect-level of 0.355mg/m(3) based on objective measurements rather than self-reported effects. Two uncertainty factors were applied to take into account both intra-species variability and the use of a concentration with an effect rather than a no-observed-adverse-effect-level. A toxicity reference value of 4x10(-3)mg/m(3) for nitrogen trichloride is proposed for repeated short exposures. Alternative values based on animal data range from 0.01 to 0.03mg/m(3).