Chemical Exposure Levels Research Articles

Insights into the Quantitative Relationship between Sensitization and Challenge for Allergic Contact Dermatitis Reactions

The ability of chemical or pharmaceutical agents to induce allergic contact dermatitis (ACD) is of major health and regulatory concern. As such, tests to identify their sensitizing capacity, such as the guinea pig maximization test and the more recently developed local lymph node assay, are broadly used. Ideally, for risk assessment it is useful to translate results from animal data into establishing safe or no-effect levels for occupational or environmental agents. This, of course, would require consideration of the quantitative relationships between sensitizing and challenge doses as well as other exposure conditions. In the present studies, we modeled two sensitizers, 2,4-dinitrochlorobenzene and squaric acid dibutyl ester, over a large range of concentrations using the LLNA and more traditional tests that measure both sensitization and elicitation responses. Both the sensitization and challenge phases provided similar dose–response curves, demonstrating a threshold followed by a shallow linear increase and eventual plateau at increasing doses. Extending earlier studies by P. S. Friedmann (1994, Immunotoxicology and Immunopharmacology, pp. 589–616, Raven Press, New York) in humans, we observed that the minimum dose required to elicit sensitization or challenge was not static, but rather reflected a “sliding-scale.” That is, as the sensitization dose was increased, the concentration required to elicit a challenge response was decreased. Correspondingly, as the challenge dose was increased, the dose required for sensitization was lessened. Taken together, these findings indicate that there is a need to consider dose–response relationships for sensitization and challenge in establishing minimum exposure levels for chemicals that cause ACD.

Differential Sensitivity of Children and Adults to Chemical Toxicity: I. Biological Basis

Children, particularly neonates, can be biologically more sensitive to the same toxicant exposure on a body weight basis than adults. Current understanding of the rates of maturation of metabolic capability and evidence from case examples on pharmaceuticals, drugs of abuse, environmental contaminants, and dietary and endogenous agents indicate that human infants up to approximately 6 months of age are typically—but not always—more sensitive to chemical toxicity than adults. For most chemicals, the immaturity of infant biotransformation, elimination, and other physiologic systems usually produces higher blood levels for longer periods. There is metabolic capacity for most tested substances in the newborn, although it is quite low and immature for some chemicals. For some chemicals, unique metabolic pathways not available in the adult human can also be utilized by the newborn. The newborn's metabolic capacity rapidly matures and, by about 6 months of age, children are usually not more sensitive to chemical toxicity than adults. By then, most metabolic systems are reasonably mature, becoming almost completely capable by 1 year of age. In many cases children are less sensitive than adults. Whether children are at greater risk from chemical exposures is another question. Risk depends on both inherent sensitivity and exposure conditions. If chemical exposure levels remain below those capable of overwhelming a child's metabolic detoxification systems and producing toxicity, children will be at no greater risk than are adults. Children of all ages are still developing so even if they are exposed to chemicals at levels below those of adults, they may be at greater risk than adults. However, as long as those exposure levels are still below those required to produce toxicity, children will not be at greater risk.

Do genotype responses always converge from lethal to nonlethal toxicant exposure levels? Hypothesis tested using clones ofDaphnia magnastraus

This study examines the hypothesis that genotypic differences in tolerance will converge with decreasing levels of toxicity: from lethal to sublethal responses and from high to low sublethal exposure levels of toxic chemicals. Four laboratory Daphnia magna clones and three chemicals with different modes of action and known sublethal effects—cadmium, copper, and fluoranthene—were selected to test the previously mentioned hypothesis. Specifically, we compare how genetic variability in feeding responses among the studied Daphnia clones changed across increasing nonlethal exposure levels (expressed as increased exposure levels of feeding inhibition, EC) and how these changes converge relative to acute lethal responses (expressed in terms of the 48-h LC50). Our data show that cadmium fully supports the convergence hypothesis and that data with fluoranthene may also support it. Nevertheless, the most important findings of the present study are to have provided experimental evidence that (1) lethal responses in acute exposures and sublethal responses such as feeding inhibition are not related, (2) genetic variability for sublethal responses tend to be lower than acute responses, and (3) trade-offs between low and high sublethal exposure levels rather than genetic heterogeneity governed sublethal responses. The first two findings have important implications for risk assessment if further supported with more data on other toxicants and clones since they suggest that concerns voiced about the need to include more genetic variability in chronic toxicity tests may be groundless. The third finding may indicate that selection under low and variable environmental levels of toxicants with sublethal effects of feeding may select genotypes with high phenotypic plasticity in response to toxic stress rather than genotypes that perform well within particular toxicant exposure levels.

Risk assessment of neurotoxic pesticides.

In order to establish safe exposure levels for toxic chemicals, risk assessment guidelines have been developed. A compilation is given by the author on the elements of risk assessment of hazardous neurotoxic pesticides, using data obtained from human epidemiological studies, from animal experiments, from the international literature and from the author's own experiments as well. Well-controlled laboratory studies of neurotoxicity have the potential to provide adequate exposure and effect data for accurate hazard identification. Animal models of neurotoxicity as highly sensitive behavioral and neurophysiological methods as a function of doses, provide data for human low dose extrapolation by using mathematical models. This procedure might be the basis for reducing risk ("risk management"), therefore some examples are given, how to handle properly neurotoxic pesticides with different- high or low-risk.

Proactive approach for the evaluation of fetal safety in chemical industries

Women, their families, and employers are concerned about potential fetal risks that may be associated with occupational exposure to chemicals. In an attempt to quantify potential fetal risks in the petroleum industry, we conducted a literature review of selected chemical compounds to which Imperial Oil Limited (IOL) female personnel may be exposed. Medline, Toxline, and Dissertation Abstracts databases were utilized to search for all research papers published in any language from 1966-1996. Chemical exposures in these papers were compared to IOL chemical exposure indices from a specific refinery and chemical plant. In total, 559 studies obtained from the literature search related to the chemicals used in a specific refinery and chemical plant. Of these, only 21 studies explicitly stated some sort of exposure level for the various chemicals. Most of the selected female reproductive toxicology studies summarized explicitly stated chemical exposure levels: either as parts per million, stratifying as to number of days of exposure, or as estimates of the percentage of the threshold limit value. On comparing the occupational literature that presented either actual or estimated values of chemical exposure dose with the IOL routine rating factors in IOL's Products and Chemicals Divisions, we found that IOL chemical exposure levels overall were lower than those reported in the literature to be associated with fetal risks. A new proactive approach is presented to inform female workers and their families of the relative safety/risk of routine occupational exposures. This approach allows for the mitigation of the misperception of teratogenic risk and unjustified fears associated with it.

‘Multiple Chemical Sensitivity’, the relevance of toxic, neurobiological and psychic effect mechanisms

The review deals mainly with the key question of chemical causation of multiple chemical sensitivity (MCS). There are only few human studies with valid information on chemical exposure and in no study the chemical toxic causation hypothesis is supported. The animal model of olfactory-limbic/neural sensitization is of heuristic value to explain MCS phenomena and includes both chemical and non-chemical Stressors. However, in animal studies seldom chemical substances and exposure levels were used which might be of relevance in the formation of MCS. The problem is demonstrated for toluene exposures in human and animal sensitization studies. In accordance with the sensitization hypotheses, human studies prove a generalized vulnerability to environmental stimuli in subjects with self-reported MCS. However, study designs do not allow to deduce whether the strong responsivity is a premorbid or comorbid phenomenon or is related to exposure. Alternative study approaches to evaluate dose-response relationships are proposed.

Health effects of environmental contaminant exposure: an intrafile comparison of the Trichloroethylene Subregistry.

The establishment of the National Exposure Registry represents the first major effort toward longitudinal surveillance of general populations exposed long-term to low levels of specific substances in the environment. The authors investigated the National Exposure Registry's Trichloroethylene Subregistry intrasubregistry differences with respect to health outcomes and the possible relationships with types and levels of chemical exposure. Investigators divided the 4041 living members of the Trichloroethylene Subregistry into 4 subgroups, by type(s) of exposures (chemicals) and duration and level of exposures. The authors compared the reporting rates for 25 health outcomes across subgroups. The authors used logistic regression, in which age, sex, education, smoking history, and occupational history were the covariates. Statistically significant increases in reporting rates were seen with (a) increased maximum trichloroethylene exposures for the outcome stroke, (b) increased cumulative chemical exposure for respiratory allergies, and (c) duration of exposure for hearing impairment. Consistently elevated reporting rates across the exposure subgroups were seen for hearing impairment, speech impairment, asthma and emphysema, respiratory allergies, and stroke. Reporting rates for urinary tract disorders were related only to cumulative chemical levels. The authors noted that there appeared to be a relationship between trichloroethylene and reporting rates for speech impairment, hearing impairment, and stroke and between volatile organic compounds and asthma and emphysema, respiratory allergies, and urinary tract disorders.

Chemical exposure in hairdresser salons: Effect of local exhaust ventilation

Although several studies demonstrate adverse health effects among hairdressers that may be related to their working environment, relatively few studies have described the chemical exposure levels in hairdresser salons. This paper shows the exposure level of isopropanol, ethanol, toluene, phenylendiamines, diaminotoluene and ammonia in six hairdresser salons, and the effect of local exhaust ventilation on these exposure levels.Stationary measurements were performed at the mixing location in the hairdresser salons. At this location isopropanol was found to be in the range from 0.7–15 mg/m3, ethanol in the range from 4–36 mg/m3 and toluene from 0.04-0.11 mg/m3. The range of ammonia in the same area was from 0.1-1.2 mg/m3.Personal monitoring of the hairdresser showed an exposure level of ammonia in a range from 0.3–10 mg/m3. Phenylendiamines and diaminotoluene were not detected.The exposure level was significantly lower in the salons with local exhaust ventilation than in the salons with no ventilation.

Chemical Exposure in Hairdresser Salons: Effect of Local Exhaust Ventilation

Although several studies demonstrate adverse health effects among hairdressers that may be related to their working environment, relatively few studies have described the chemical exposure levels in hairdresser salons. This paper shows the exposure level of isopropanol, ethanol, toluene, phenylendiamines, diaminotoluene and ammonia in six hairdresser salons, and the effect of local exhaust ventilation on these exposure levels. Stationary measurements were performed at the mixing location in the hairdresser salons. At this location isopropanol was found to be in the range from 0.7-15 mg/m3, ethanol in the range from 4-36 mg/m3 and toluene from 0.04-0.11 mg/m3. The range of ammonia in the same area was from 0.1-1.2 mg/m3. Personal monitoring of the hairdresser showed an exposure level of ammonia in a range from 0.3-10 mg/m3. Phenylendiamines and diaminotoluene were not detected. The exposure level was significantly lower in the salons with local exhaust ventilation than in the salons with no ventilation.

Effect of noise and solvents on hearing: Findings from three field studies

A holistic approach to studying the workplace as a combination of physical, chemical, biological, and organizational factors is receiving growing attention. This approach includes initiatives to investigate the potential interaction between noise and chemicals. NIOSH has conducted three cross-sectional studies on the effects of solvents on hearing, alone or in combination with noise. Audiometric thresholds were compared with ISO 1999 estimates, and the prevalence, risk ratios, and predicted probability of developing a hearing loss were calculated. In all of the investigations, solvent mixtures which had toluene as a main component were found to affect the hearing of workers exposed to low noise levels. Considering the multiplicity of chemicals that are used occupationally and evidence that some are ototoxic, it is conceivable that numerous populations are being underserved regarding hearing loss prevention since the permissible exposure levels for chemicals do not take into account their potentiation of hearing loss. Workers who are exposed to A-weighted noise levels below 85 dB time-weighted average are not required to be included in hearing conservation programs. Furthermore, methods currently used in hearing conservation (e.g., hearing protectors and noise control) may be insufficient, or even inappropriate, for workers exposed to both chemicals and noise.

SUBACUTE EXPOSURE TO 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) IN GERIATRIC MICE: EFFECTS IN THYMIC, SPLENIC, AND BONE MARROW HEMATOPOIETIC CELLS

Exposure of geriatric m ice (21- 1 m o) to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produced alterations in thymus, spleen, and bone m arrow hematopoietic cell populations. Female C57BL/ 6 mice were dosed (via intraperitoneal injection) with 0, 5.0, or 10.0 ug/ kg TCDD in corn oil for 5 consecutive days. Evaluation of imm une endpoints took place on the second day following cessation of dosing. A limited but significant reduction in bone marrow cellularity was produced by exposure to TCDD at 10.0 ug/ kg, in the presence of unaltered percentages of cells expressing CD45, CD45R, and Mac-1 antigens. A lim ited increase in splenic cellularity was also present at the higher dose level of TCDD, where trends toward reduced percent++ ages of CD45R B cells and Thy 1.2 T cells were observed but did not reach significance. Pronounced, dose-dependent thymic hypocellularity was evident at both levels of chemical exposure in the aged m ice, and was accom panied by+ + decreased percentages of CD4 CD8 (double positive, DP) cells and concomitant--- + increased percentages of CD4 CD8 (double negative, DN) and CD4 CD8 (single positive, SP) cells. The total numbers of thymocytes in all four phenotypes defined by CD4 and CD8 antigens decreased significantly in treated animals, an apparent reflection of the chem ical-induced hypocellularity. These results indicate that, sim ilar to perinatal and young adult m odels, the geriatric murine thym us may be a highly sensitive target of TCDD exposure.

NIOSH Is Focusing On Practical Ways To Protect Workers

For years, the National Institute for Occupational Safety & Health (NIOSH)—the only federal agency that conducts research on the health and safety of workers—had an ivory tower image. It was known for publishing criteria documents that were strong scientifically but offered few practical solutions to workplace hazards. But over the past few years, the agency has become far more down-to-earth. It is working with associations of small businesses, labor unions, and other groups to develop feasible guidelines on appropriate exposure levels for chemicals and other agents. And rather than focus entirely on assessing the risks of exposure, it is putting a great deal of effort into developing engineering controls that small and large businesses can afford. Much of workers' exposure to chemicals and other agents such as noise occurs in small businesses. These companies do not have the resources to hire industrial hygienists, nor do they have the skills or money to design engineering solutions ...

Air Force approach to risk assessment for Halon replacements

Finding safe, environmentally acceptable, and effective replacements for Halon fire-extinguishing agents and other chemicals banned by the Montreal Protocol is a formidable task for Air Force research and development organizations. One factor that makes this task a challenge is the uncertainty in relating toxicology studies in laboratory animals to the human situation. This uncertainty from toxicology studies affects the risk assessment process by calling for very conservative decisions. Because of this uncertainty, public pressure and politics also impact the regulatory process. The Air Force approach to assessing health hazards for Halon replacements is to provide scientific information that directly applies to the parts of the extrapolation process that are responsible for the most uncertainty. Most regulatory agencies readily incorporate scientific information, when it is available, which can reduce uncertainty. These Air Force studies will be used to provide realistic exposure levels for replacement chemicals which will allow mission accomplishment and provide safety for the worker and the populace.

A tier approach for evaluating the respiratory allergenicity of low molecular weight chemicals

A multi-level approach for evaluating low molecular weight chemicals as respiratory sensitizers is proposed. The approach involves four levels of testing that utilize both in vitro and in vivo methods. Tier 1 evaluates structure-activity information to determine if the chemical can covalently modify carrier molecules. It also includes a literature search to determine if the compound belongs to a family of chemicals that has been reported to induce hypersensitivity. Tier 2 tests the chemical's potential to haptenate carrier molecules (i.e., protein) under in vitro conditions. Positive results in Tiers 1 and 2 lead to testing in a guinea pig injection model to assess chemical immunogenicity (Tier 3). A positive result at this level leads to testing in a guinea pig inhalation model to address questions about relevant routes of chemical exposure and allergenicity (Tier 4). Tier 4 results are used in determining safe chemical exposure levels. We have evaluated three chemicals using this scheme: phthalic anhydride, reactive black b dye, and toluene diisocyanate. All three have reactive groups and haptenate protein in vitro. They induce a humoral immune response when injected into guinea pigs at equimolar concentrations, and they sensitize animals via inhalation exposure. The severity of the response (antibody titer and respiratory reactivity) can be used to rank-order the chemicals in terms of allergenic “potency.” Our data indicate that this approach can detect chemical allergens and can be used to characterize them as moderate or strong respiratory sensitizers.

OSHA's Proposed Air Contaminant Rule Draws Strong Criticism

The Occupational Safety & Health Administration's proposed massive revision of permissible exposure levels for hundreds of chemicals in the workplace is taking a beating during the more than two weeks of public testimony on the proposal. Many witnesses have assailed the levels proposed for individual substances, but many also have been critical of the methods the agency used for the entire regulation. When OSHA was first set up, one of its early actions to protect workers from exposures to hazardous chemicals was to adopt in 1971 a regulation on permissible exposure levels for many chemicals that had been developed by the American Conference of Governmental Industrial Hygienists (ACGIH). In the ensuing 17 years, ACGIH has made many changes to its recommendations, adding new chemicals to its list of hazardous workplace chemicals and lowering the safe exposure levels for others. The OSHA levels, however, did not change, and are still the same as set in 1971. ...

Chemical, Physical, and Genetic Factors Interfering with DNA Repair-a Review

Because of its function as transmitter of genetic information, DNA is the most important macromolecule in need of protection from attack by chemical and physical agents, but mechanisms have evolved for repairing such damage to DNA. The presence of the adaptive response and other cellular repair systems (excision, post-replication, SOS, etc.) diminishes the toxicologic effects of low doses of toxic or muta-genic substances. Whether or not these genotoxic effects can be reduced to undetectable levels is not certain. Nonetheless, this repair-mediated diminution of damage due to chemicals constitutes one of the arguments in favor of existence of “safe” threshold levels of chemical exposure (Schendel, 1981). In turn, the repair process itself may be affected by chemical and physical agents. To determine the mode of action of a specific compound on the process of DNA repair becomes complex when all factors are taken into consideration. There are agents which interfere with DNA repair but they are also as active or more active in suppressing replicative DNA synthesis, as well as RNA and protein synthesis. The interference with repair may arise from other major processes such as alteration of energy metabolism and effects on precursor pathways and/or enzymatic cofactors. Whether or not an agent can specifically inhibit DNA repair enzymes has not been answered. The point must be made, however, that this type of interference with essential protective mechanisms is taking place and it may change anticipated outcomes of chemical or physical exposures. The magnitude of this effect due to the exposure of people to so many chemicals should be recognized and studied for their degree of interference with all the processes of DNA repair.