Adolf Vyskocil

Assessment of molybdenum toxicity in humans

In an attempt to define a tolerable daily intake (TDI) for molybdenum based on a toxicological risk analysis approach, a large literature survey was conducted. In man, absorption of molybdenum after oral intake is in the range of 28–77% and urinary excretion is 17–80% of the total dose. A low order of toxicity of molybdenum compounds has been observed in humans. However, with the available data, it is not possible to calculate any dose–response or dose–effect relationships. Because molybdenum toxicity is associated with copper intake or depleted copper stores in the body, humans who have an inadequate intake of dietary copper or some dysfunction in their copper metabolism that makes them copper‐deficient could be at greater risk of molybdenum toxicity. In the absence of relevant human studies, animal studies were evaluated for the derivation of the TDI. Effects of Mo on reproduction and foetal development were found to be critical effects observed in rats and mice. A dose–response relationship was observed in a study by Fungwe et al., with a ‘no observed adverse effect’ level (NOAEL) and a ‘lowest observed adverse effect’ level (LOAEL) of 0.9 and 1.6 mg Mo kg−1 day−1, respectively. Applying uncertainty factors of 10 for intraspecies and 10 for interspecies differences to the NOAEL, a TDI of 0.009 mg Mo kg−1 day−1 was calculated. The TDI is given a medium confidence rating. This TDI is more than double the upper limit of adequate intake for adolescents and adults that was derived from the Mo content of the average diet in the USA. Copyright

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.

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.

Chronic Nephrotoxicity of Soluble Nickel in Rots

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-β-D-glucosaminidase (NAG), albumin and β2-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 μg 24 h-1 for female rats (P<0.05) and 989 and 2065 μg 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.

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 LC50 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 identi-fied as no-observed-effect level (NOEL) and no-observed-adverse-effect level (NOAEL) for pathological and histo-logical 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.

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.

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 μg 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, β2microglobulin (β2-m) and retinol-binding protein (RBP) in males and lysozyme in females. Lysozyme and N-acetyl-β-D-glucosaminidase (NAG) were increased in male and total proteins, β2-m, NAG and RBP in female exposed workers. Significant correlations between urinary concentrations of nickel on one side and that of β2-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.

Risk assessment of lung cancer related to environmental PAH pollution sources

We assessed the lung cancer risk in six localities with aluminium smelting activities and five with other polycyclic aromatic hydrocarbon (PAH) pollution sources, using two quantitative risk assessment (QRA) approaches for PAH mixtures and compared their risk predictions against actual cancer incidence. In the first approach, carcinogen exposure was estimated from animal-derived BaP toxic equivalents (BaPeq) of individual PAHs. The upper bound lifetime risk estimates ranged between 0.012-4.7×10-5 and 0.019-0.94×10-5 in the aluminium and other localities, respectively. The second approach assumed that the potency of PAH mixtures was linked to their BaP content and lifetime lung cancer unit risk gradients were estimated from epidemiological studies based on BaP exposure measurements. Lifetime risks ranged between 0.02-89×10-5 and 0.06-6.8×10-5 in the aluminium and other localities, respectively. Predicted risks were generally higher in smelter towns, and higher when based on epidemiological studies than on BaPeq. In smelting communities, there was a linear relationship (R2≈0.8) between female lung cancer rates and PAH exposure estimates. To conclude, animal/BaPeq-based QRAs predicted lower risks than occupational/BaP-based QRAs. Epidemiological validation of the QRA could be performed for elevated past exposure to PAHs, but not for currently lower concentrations.

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 nick el 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 absorp tion).

A Web Tool for the Identification of Potential Interactive Effects of Chemical Mixtures

This project was undertaken to develop a toxicological database allowing the identification of possible additive or other interactive effects of mixtures present in the work environment. In the first phase of the project, whose findings have already been published, critical toxicological data were compiled for each of the 695 chemical substances in the Quebec Occupational Health Regulation, allowing the prediction of potential additivity among components of a mixture. In the second phase of this project, the types of interactions for mixtures most likely to be found in workplaces and for which primary literature data are available were specified. The toxicological data were evaluated only for realistic exposure concentrations up to the short-term exposure limit or ceiling value or five times the 8-hr time-weighted average (TWA) permissible exposure limit (PEL) for human data and up to 100 times the 8-hr TWA PEL or ceiling value for animal studies. In total, 675 studies were evaluated covering 209 binary mixtures of substances. For the majority of cases where potential additivity was identified in Phase 1, there is a lack of toxicological data in the primary literature. In these cases, the results of the first phase will be useful as the default hypothesis. The resulting database integrates the results from both phases of the project. A web-based computer tool allows the user to determine whether there is potential additivity or interaction among components of a mixture.