A weight of evidence approach for the assessment of the ototoxic potential of industrial chemicals.

There is accumulating epidemiological evidence that exposure to some solvents, metals, asphyxiants and other substances in humans is associated with an increased risk of acquiring hearing loss. Furthermore, simultaneous and successive exposure to certain chemicals along with noise can increase the susceptibility to noise-induced hearing loss. There are no regulations that require hearing monitoring of workers who are employed at locations in which occupational exposure to potentially ototoxic chemicals occurs in the absence of noise exposure. This project was undertaken to develop a toxicological database allowing the identification of possible ototoxic substances present in the work environment alone or in combination with noise exposure. Critical toxicological data were compiled for chemical substances included in the Quebec occupational health regulation. The data were evaluated only for noise exposure levels that can be encountered in the workplace and for realistic exposure concentrations up to the short-term exposure limit or ceiling value (CV) or 5 times the 8-h time-weighted average occupational exposure limit (TWA OEL) for human data and up to 100 times the 8-h TWA OEL or CV for animal studies. In total, 224 studies (in 150 articles of which 44 evaluated the combined exposure to noise and a chemical) covering 29 substances were evaluated using a weight of evidence approach. For the majority of cases where potential ototoxicity was previously proposed, there is a paucity of toxicological data in the primary literature. Human and animal studies indicate that lead, styrene, toluene and trichloroethylene are ototoxic and ethyl benzene, n-hexane and p-xylene are possibly ototoxic at concentrations that are relevant to the occupational setting. Carbon monoxide appears to exacerbate noise-induced hearing dysfunction. Toluene interacts with noise to induce more severe hearing losses than the noise alone.

Occupational ototoxicity of n-hexane.

The ability of chemicals to produce hearing loss themselves or to promote noise-induced hearing loss has been reported for some organic solvents. The objective of this study was to review the literature on the effects of low-level exposure to n-hexane on the auditory system and consider its relevance for occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the permissible inhalation exposure limits. In Quebec, the time-weighted average exposure value (TWAEV) for 8 h is 50 ppm. In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at five times the TWAEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. There is no convincing evidence of n-hexane-induced hearing loss in workers. In rats, n-hexane seems to affect auditory function; however, the site of these alterations cannot be determined from the present data. Further studies with sufficient data on the exposure of workers to n-hexane are necessary to make a definitive conclusion. In the interim, we recommend considering n-hexane as a possibly ototoxic agent.

Ototoxicity of trichloroethylene in concentrations relevant for the working environment.

Organic solvents can cause hearing loss themselves or promote noise-induced hearing loss. The objective of this study was to review the literature on the effects of low-level exposure to trichloroethylene on the auditory system and consider its relevance for the occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the Quebec permissible exposure limits: 50 ppm 8-h time-weighed average exposure value (TWAEV) and 200 ppm short-term exposure value (STEV). In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at the STEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. There is no convincing evidence of trichloroethylene-induced hearing losses in workers. In rats, trichloroethylene affects the auditory function mainly in the cochlear mid- to high-frequency range with a lowest observed adverse effect level (LOAEL) of 2000 ppm. No studies on ototoxic interaction after combined exposure to noise and trichloroethylene were identified in humans. In rats, supra-additive interaction was reported. Further studies with sufficient data on the trichloroethylene exposure of workers are necessary to make a definitive conclusion. In the interim, we recommend considering trichloroethylene as an ototoxic agent.

Lack of renal changes in stainless steel welders exposed to chromium and nickel.

Biochemical markers of kidney damage were examined in 52 male stainless steel welders (manual metal arc welding) exposed to chromium and nickel. No difference was found in the mean urinary excretion of total proteins, albumin, protein 1, transferrin, retinol-binding protein, lactate dehydrogenase, lysozyme, or beta-N-acetylglucosaminidase in a comparison with matched referents. Beta 2-microglobulin was slightly increased in those welders with a urinary chromium concentration of greater than 64.5 nmol.mmol-1 creatinine. The prevalences of abnormal values did not differ from those observed in the reference group. No correlation was found between the concentrations of chromium or nickel in urine and that of proteins or enzymes. No consistent or clinically significant renal impairment was revealed among the stainless steel welders exposed to a chromium air concentration slightly above the current threshold limit value of the American Conference of Governmental Industrial Hygienists for water-soluble hexavalent chromium compounds (50 micrograms.m-3).

Patterns of 1-hydroxypyrene excretion in volunteers exposed to pyrene by the dermal route.

The urinary excretion profiles following exposure to pyrene were established in one psoriasic patient under treatment with a coal tar-based shampoo and in two other volunteers exposed to a single dose of 100 microliters creosote and, in a separate experiment, to five consecutive daily dermal applications of 500 micrograms pyrene on 200 cm2 of the inner face of the forearms. Timed micturitions were collected for up to 48 h following exposure. Both in the psoriasic patient and in the volunteers exposed to creosote, the excretion peaks between 10 and 15 h after application and first-order apparent half lives of 11.5-15 h can be calculated for the elimination phase. Compatible with these observations, repeated exposure to pyrene in the volunteers causes an increase in peak and trough urinary 1-hydroxypyrene (1-OHP) values for the first few days following the first exposure. These results suggest that the difference between beginning-of-shift/beginning of work week and beginning-of-shift/end of work week 1-OHP excretions should reflect the average exposure of the week in workers having a constant exposure to pyrene. The difference between the beginning- and end-of-shift excretion values of a given day should reflect the exposure of that day but the maximum excretion would be attained a few hours after termination of exposure.

Background urinary 1-hydroxypyrene levels in non-occupationally exposed individuals in the Province of Québec, Canada, and comparison with its excretion in workers exposed to PAH mixtures.

The urinary excretion of 1-hydroxypyrene (1-OHP) was measured in two reference groups of non-occupationally exposed individuals and in four groups of workers. Two of these groups were exposed to what were considered to be low levels of polycyclic aromatic hydrocarbons (PAH) on the basis that even post-shift 1-OHP excretion values were low (< 2 mumol/mol creatinine). Therefore, urine samples were collected from these workers after a period of > 60 h without occupational exposure which should yield values approaching background levels. Pooling these results with those of the reference groups yielded a total of 140 individuals having a mean (geometric) excretion of 0.08 mumol/mol creatinine and 5th, 50th and 95th percentiles of 0.02, 0.09 and 0.32 mumol/mol creatinine. The mean (geometric) excretion in the 95 nonsmokers and 45 smokers of this pool was 0.07 and 0.12 mumol/mol creatinine, respectively (one-tailed Student t-test, P < 0.001). Both this background excretion and the contribution of smoking appeared small in comparison with the excretion levels observed in some groups of exposed workers. Indeed, creosote workers described in this report had a geometric mean (range) excretion of 1.63 (0.18-10.47) mumol/mol creatinine during their working week. It is concluded that, for the biological monitoring of workers exposed to PAH, urinary 1-OHP appears to be a useful bioindicator for which background environmental contamination or smoking habits can be neglected in most cases.

Urinary excretion kinetics of 1-hydroxypyrene in volunteers exposed to pyrene by the oral and dermal route.

Two well-informed human volunteers were exposed to 500 micrograms pyrene by ingestion and by dermal application, in two separate experiments. Urinary measurements of 1-hydroxypyrene (1-OHP) were performed on all micturitions taken at intervals of 0.5-4 h for a total period of 48 h after dosing. Following the absorption phase, 1-OHP is excreted with a first order apparent half-life of approximately 12 h for both volunteers and both exposure routes. These results compare well with other previously published studies. A more refined analysis of the data was performed using a two-compartment toxicokinetic model for 'pyrene' (its fraction eventually excreted as 1-OHP). As it was found that a classical first-order system did not adequately fit the data, a non-linear term was introduced in the model for the elimination of urinary 1-OHP. Computer iteration performed on the oral absorption data allowed an estimation of various toxicokinetic parameter values. The mean intercompartmental exchange (k12 and k21) and elimination coefficients were 0.010, 0.006 and 0.012 min-1, respectively. The first two values compare well with those previously published for the rat, whereas the latter is smaller in humans. These values were used to satisfactorily simulate the experimental data for both routes of exposure, adjusting only for kabs which was estimated at 0.014 and 0.0029 min-1 for the oral and dermal exposure, respectively. The proposed model generates new hypotheses on the metabolism of pyrene. The information collected will contribute to the validation of the utilisation of 1-OHP as a biological indicator of exposure to pyrene.

Peroxyacetyl nitrate: review of toxicity.

PAN is one of a class of common air pollutants formed by the action of sunlight on volatile organic compounds and nitrogen oxides. No toxicokinetic studies have been found in the available literature. The acute toxicity of PAN is less than that of ozone, similar to NO2 and higher than SO2. The LC30, in mice and rats were 718-743 mg/m3 (for 2 h) and 470 mg/m3 (for 4 h), respectively. Following acute exposure, severe lung lesions and, at the higher levels, damage to the epithelium of upper parts of the respiratory tract were found in animals. It seems that concentrations of 1.19-1.49 mg/m3 lie not far from the threshold required for pulmonary function effects in sensitive individuals. However, these PAN concentrations are well above the maximum ambient concentrations usually experienced within the USA and Canada (0.003-0.078 mg/m3). It appears unlikely that present ambient PAN concentrations would affect pulmonary functions responses to ambient ozone. In human, the lowest level causing eye irritations was 0.64 mg/m3 for 2 h. Concentrations of 0.99 and 4.95 mg/m3 were identified as no-observed-effect level (NOEL) and no-observed-adverse-effect level (NOAEL) for pathological and histological changes in the respiratory system (nasal passages) of rats during subchronic exposures to PAN, but were not considered to be relevant to derivation of a RfC for chronic inhalation exposure. PAN is a weak point mutagen or clastogen. The data are not sufficient to evaluate its carcinogenicity. No study was found which could be used for the derivation of a RfC for acute or chronic inhalation exposure to PAN.

Chronic nephrotoxicity of soluble nickel in rats.

1. Male and female Wistar rats were given 100 mg L-1 of nickel (as nickel sulfate) in drinking water for 6 months. Lactate dehydrogenase, total proteins, N-acetyl-beta-D-glucosaminidase (NAG), albumin and beta 2-microglobulin were measured in 24 h urine after 3 and 6 months of exposure. Body and kidney weights were also recorded. 2. After 6 months, urinary excretion of albumin in control and exposed rats was 354 and 1319 micrograms 24 h-1 for female rats (P < 0.05) and 989 and 2065 micrograms 24 h-1 for male rats (P = non significant). Kidney weights were significantly increased in the exposed groups. No significant changes were observed in other parameters. 3. The results suggest that low-level oral exposure to soluble nickel either induces changes of glomerular permeability in female and possibly in male rats, or enhances the normal age-related glomerular nephritis lesions of ageing rats. The intake was probably not high enough to induce significant tubular changes. The female rat seems to be more sensitive to the nephrotoxic effect of nickel than the male rat.

Distribution of nickel in body fluids and organs of rats chronically exposed to nickel sulphate.

1. Male and female rats were given 100 mg Ni L-1 (as nickel sulphate) in drinking water for 6 months. 2. The feeding of nickel was associated with an increased concentration of nickel in body fluids and organs. The highest concentrations of nickel were found in the liver of both male and female rats. In male rats nickel levels decreased in the order: liver > kidney = whole blood = serum > testes > urine. In female rats the decreasing order was similar: liver > kidney = whole blood = serum = plasma > urine > ovaries. 3. No significant differences were found between nickel concentrations in organs (except ovaries), blood and urine of rats exposed for 3 months and those exposed for 6 months indicating the reaching of a steady state of nickel in the rat during long-term exposure. 4. The urinary excretion of the orally administered nickel was only 2% of absorbed dose (supposing 1% Ni absorption).

Environmental exposure to polycyclic aromatic hydrocarbons in Czech Republic.

1 Objectives of this study were (1) to compare concentrations of individual polycyclic aromatic hydrocarbons (PAH) in air of polluted and nonpolluted area of Czech Republic during winter and summer periods and (2) to verify if urinary 1-hydroxypyrene (1-OHP), as supposed practical biological marker, permits the assessment of spacial and temporal variations in environmental PAH exposure. 2 The study population consisted of three groups: (1) a group of 22 physical exercise students who regularly train outside, from the university situated in a polluted town, spending 14 days in winter and 14 days in summer in 'non-polluted' mountains; (2) a control group of 22 residents from the town and (3) a control group of 18 residents from the mountains. 3 The total PAH concentrations (sum of 13 individual PAH) were 19.3 and 104.6 ng/m3 in town and in mountains, respectively, during summer and 86.6 and 261 ng/m3 during winter. 4 Median 1-OHP levels ranged between 0.03 and 0.13 mumol/mol creatinine for controls and between 0.04 and 0.12 mumol/mol creatinine for students. No relationship was found between pyrene levels in air and group means of urinary 1-OHP. Our results show that other factors (probably PAH in food) contribute in masking air pollution influence on urinary 1-OHP levels in subjects non-occupationally exposed to PAH.

Biochemical renal changes in workers exposed to soluble nickel compounds.

1. Biochemical markers of kidney damage were examined in 14 male and 12 female workers highly exposed to soluble nickel compounds in a chemical plant. The results were compared to those obtained in 12 male and 12 female matched controls. 2. The concentration of nickel in urine of male and female workers averaged 5.0 and 10.3 micrograms g-1 creatinine, respectively. The mean duration of exposure in male and female workers was 25 and 15 years. 3. No difference was found in the mean urinary excretion of lactate dehydrogenase, albumin and transferrin in both sexes, total proteins, beta 2-microglobulin (beta 2-m) and retinol-binding protein (RBP) in males and lysozyme in females. Lysozyme and N-acetyl-beta-D-glucosaminidase (NAG) were increased in male and total proteins, beta 2-m, NAG and RBP in female exposed workers. Significant correlations between urinary concentrations of nickel on one side and that of beta 2-m in women (r = 0.462, P = 0.022) and men (r = 0.41, P = 0.018) and of NAG in men (r = 0.405, P = 0.019) on the other side were found in exposed subjects. 4. Results indicate adverse effects of soluble nickel compounds on the kidney tubular function. In agreement with literature data it seems that those effects occur only at high exposure levels.

Study on kidney function in female workers exposed to perchlorethylene.

1. Biochemical markers of kidney damage were examined in 16 female workers chronically exposed to tetrachlorethylene (TCE) in five dry-cleaning shops. The results were compared with those obtained in 13 females non-occupationally exposed to organic solvents. 2. The intensity of exposure was monitored by personal environmental monitoring. The time-weighed average exposure to TCE amounted to 157 mg m-3 (range 9-799 mg m-3). A satisfactory agreement was found between the concentration of TCE in ambient air sampled with the charcoal tube method and with a passive dosimeter. 3. The urinary excretion of lysozyme was increased in the exposed group. No difference was found in the urinary excretion of albumin, beta 2-microglobulin, lactate dehydrogenase, total proteins or glucose. The prevalence of abnormal values of biochemical parameters in the exposed group did not differ from that observed in the control group. No correlation was found between the level of TCE exposure and biochemical parameters. 4. The present study suggests that chronic exposure to TCE does not lead to renal damage.

Effects of peak concentrations on the neurotoxicity of styrene in volunteers.

The manufacture of fibreglass reinforced plastic products may give rise to substantial peak exposures to styrene. Such exposure patterns need further consideration in terms of styrene neurotoxicity. The aim of this study was to evaluate the neurotoxic effects of short-term peak exposures in volunteers, at levels respecting the Quebec occupational exposure limits (8 hours time weighed average of 213 mg/m3 and 15 min average of 426 mg/ m3). The volunteers had not been previously exposed to styrene and they had no documented exposure to known neurotoxicants during the study. Twenty-four volunteers were exposed to five exposure scenarios during 6 hours: a, stable exposure to 106 mg/m3; b, variable exposure with a mean concentration of 106 mg/m3 with four 15 min peaks mounting up to 213 mg/m3; c, stable exposure to 213 mg/m3; d, variable exposure with a mean concentration of 213 mg/m3 and four peaks of 426 mg/m3 and e, two stable exposures to 5 mg/m3 (control). Before and after each exposure scenario, volunteers were submitted to a battery of sensory tests (visual and olfactory), neuropsychological tests (reaction time, attention, memory, psychomotor function), and self-evaluation questionnaires (mood and symptoms) in a test-retest design. The results show that the different exposure scenarios involving peak exposures did not influence either the performance to any test or subjective signs and symptoms. However, due caution must be exercised in extrapolation of the current results to occupational exposure since only acute exposures were tested and volunteers were at rest during exposure, which resulted in lower doses than those experienced by physically active workers.

[Biological monitoring of chemical exposure]. / Biologické monitorování chemické expozice.

In this paper we described the biological monitoring as a capable exposure assessment tool that has provided important information used in public health decisions. Biological monitoring is based on determination of biological markers of exposure which are presented as the quantity of a chemical substance or its metabolites or as the deviation of biological parameters (enzyme activity etc.) induced by this substance in exposed humans. The greatest advantage of biological monitoring is the fact that the biological marker of exposure is more directly related to the adverse effects than any environment measurement. Another advantage of biological monitoring is based on the reality that the nonoccupational background exposure (leisure activity, residency, dietary habits, smoking, etc.) may also be expressed in the biological level. Biological parameters can be unfortunately affected by various factors that influence the fate of xenobiotic in vivo. The "BEL" (BTV-biological tolerance value for occupational exposures) is defined as the maximum permissible quantity of a chemical substance or its metabolites or the maximum permissible deviation from the norm of biological parameters during or after exposure. It should be subject to regular revision in the light of new scientific data.

[Chemical load in the population and its evaluation]. / Chemická zátez populace a její hodnocení.

Human health is determined by the interplay between heredity and the environment. Air, water, food and soil contain chemical, physical and biological agents some of which are known to be harmful to health. Chemical substances that pose the risk to human health and safety and to the environment are subject to governmental regulation. The regulatory decision-making process and regulatory actions are based on two distinct elements: risk assessment and risk management. Air pollution (outdoor, indoor) is a world problem afflicting densely populated urban centers and heavily industrialised areas. Industrialization and the widespread use of chemicals coupled with modern intensive agricultural practices have raised a global concern about the contamination of soil and water. Three categories of environmental chemical contaminants generally occur in food--natural and synthetic organic compounds and traces of toxic metals. Human health protection against chemical exposure can be realised in three ways. Environmental monitoring assesses exposure to a chemical agent by measuring its concentration in the environment (i.e., air, soil, food, water). Biological monitoring assesses internal exposure to a chemical agent by measuring the chemical, its metabolites or nonadverse biological response in body fluids, tissues, expired air or excreta. Health surveillance entails the periodic medical examinations of exposed humans with the purpose of protecting health and preventing disease.

[Polycyclic aromatic hydrocarbons. II. Toxic effects]. / Polycyklické aromatické uhlovodíky. II. Toxické úcinky.

Polycyclic aromatic hydrocarbons (PAH) represent dangerous environmental pollutants. Many of them have toxic and carcinogenic potential. Presented work summarizes most of available data on the absorption, metabolism and elimination of PAH. The second part of article contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. In the third part of article, the populations with higher susceptibility to exposure to PAH are described and the influences of chemical interaction of PAH to biological effects are mentioned.

[Polycyclic aromatic hydrocarbons. Biological indicators of exposure and possibilities of prevention]. / Polycyklické aromatické uhlovodíky. III. Biologické ukazatele expozice a moznosti prevence.

Polycyclic aromatic hydrocarbons (PAH) represent an extensive group of ubiquitous environmental pollutants disposing of a considerable toxic and carcinogenic potential. According to the IARC data (International Agency for Research on Cancer), PAH represent the largest group of chemical carcinogens produced during combustion, pyrolysis and pyrosynthesis of organic matter. PAH can be identified in atmosphere, water, soil, food and other materials which are in daily contact which the general population. Presented work summarizes most of available data on the biological markers used to identify or quantify the exposure to PAH and on the biological markers used to characterize the effects caused by PAH. The digest of possibilities of reduction toxic effects of PAH concludes the work.

[Polycyclic aromatic hydrocarbons. I. Environmental contamination and environmental exposure]. / Polycyklické aromatické uhlovodíky I. Kontaminace prostredí a expozice osob.

Polycyclic aromatic hydrocarbons (PAHs) represent danger ubiquitous environmental pollutants. A lot of them have toxic and carcinogenic potential. Presented work summarises most of available data describing properties, origin and occupational and non-occupational sources of PAHs. Contamination of environment is described separately for air, water, soil, sediments and food. Possibilities of occupational and non-occupational exposure of persons are discussed and populations with potentially high exposures to PAHs are defined. The work is concluded by digest of regulations and guidelines regarding environmental contamination of PAHs.

Ethyl benzene should be considered ototoxic at occupationally relevant exposure concentrations.

Organic solvents can produce ototoxic effects in both man and experimental animals. The objective of this study was to review the literature on the effects of low-level exposure to ethyl benzene on the auditory system and consider its relevance for the occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the permissible exposure limits. In Quebec, the Time-Weighed Average Exposure Value for 8A h (TWAEV) is 100A ppm (434A mg/m(3)) and the Short-Term Exposure Value for 15A min (STEV) is 125A ppm (543A mg/m(3)). In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at STEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. In workers, there is no evidence of either ethyl benzene-induced hearing losses or ototoxic interaction after combined exposure to ethyl benzene and noise. In rats, ethyl benzene affects the auditory function mainly in the cochlear mid-frequency range and ototoxic interaction was observed after combined exposure to noise and ethyl benzene. Further studies with sufficient data on the ethyl benzene exposure of workers are necessary to make a definitive conclusion. Given the current evidence from animal studies, we recommend considering ethyl benzene as an ototoxic agent.