Claude Viau

Guidelines for the communication of Biomonitoring Equivalents: Report from the Biomonitoring Equivalents Expert Workshop

Biomonitoring Equivalents (BEs) are screening tools for interpreting biomonitoring data. However, the development of BEs brings to the public a relatively novel concept in the field of health risk assessment and presents new challenges for environmental risk communication. This paper provides guidance on methods for conveying information to the general public, the health care community, regulators and other interested parties regarding how chemical-specific BEs are derived, what they mean in terms of health, and the challenges and questions related to interpretation and communication of biomonitoring data. Key communication issues include: (i) developing a definition of the BE that accurately captures the BE concept in lay terms, (ii) how to compare population biomonitoring data to BEs, (iii) interpreting biomonitoring data that exceed BEs for a specific chemical, (iv) how to best describe the confidence in chemical-specific BEs, and (v) key requirements for effective communication with health care professionals. While the risk communication literature specific to biomonitoring is sparse, many of the concepts developed for traditional risk assessments apply, including transparency and discussions of confidence and uncertainty. Communication of BEs will require outreach, education, and development of communication materials specific to several audiences including the lay public and health care providers.

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

Urinary 1-hydroxypyrene as a biomarker of exposure to polycyclic aromatic hydrocarbons: biological monitoring strategies and methodology for determining biological exposure indices for various work environments

This article reviews the published studies on urinary 1-hydroxypyrene (1-OHP) as a biomarker of exposure to polycyclic aromatic hydrocarbons (PAHs) in work environments. Sampling and analysis strategies as well as a methodology for determining biological exposure indices (BEIs) of 1-OHP in urine for different work environments are proposed for the biological monitoring of occupational exposure to PAHs. Owing to the kinetics of absorption of pyrene by different exposure routes and excretion of 1-OHP in urine, in general, 1-OHP urinary excretion levels increase during the course of a workday, reaching maximum values 3-9 h after the end of work. When the contribution of dermal exposure is important, post-shift 1-OHP excretion can however be lower than pre-shift levels in the case where a worker has been exposed occupationally to PAHs on the day prior to sampling. In addition, 1-OHP excretion levels in either pre-shift, post-shift or evening samples increase during the course of a work-week, levelling off after three consecutive days of work. Consequently, ideally, for a first characterization of a work environment and for an indication of the major exposure route, considering a 5-day work-week (Monday to Friday), the best sampling strategy would be to collect all micturitions over 24 h starting on Monday morning. Alternatively, collection of pre-shift, post-shift and evening urine samples on the first day of the work-week and at the end of the work-week is recommended. For routine monitoring, pre-shift samples on Monday and post-shift samples on Friday should be collected when pulmonary exposure is the main route of exposure. On the other hand, pre-shift samples on Monday and Friday should be collected when the contribution of skin uptake is important. The difference between beginning and end of work-week excretion will give an indication of the average exposure over the workweek. Pre-shift samples on the first day of the work-week will indicate background values, and, hence, reflect general environment exposure and body burden of pyrene and/or its metabolites. On the other hand, since PAH profile can vary substantially in different work sites, a single BEI cannot apply to all workplaces. A simple equation was therefore developed to establish BEIs for workers exposed to PAHs in different work environments by using a BEI already established for a given work environment and by introducing a correction factor corresponding to the ratio of the airborne concentration of the sum of benzo(a)pyrene (BaP) equivalent to that of pyrene. The sum of BaP equivalent concentrations represents the sum of carcinogenic PAH concentrations expressed as BaP using toxic equivalent factors. Based on a previously estimated BEI of 2.3 μmol 1-OHP mol(-1) creatinine for coke-oven workers, BEIs of 4.4, 8.0 and 9.8 μmol 1-OHP mol(-1) creatinine were respectively calculated for vertical pin Söderberg workers, anode workers and pre-bake workers of aluminium plants and a BEI of 1.2 μmol 1-OHP mol(-1) creatinine was estimated for iron foundry workers. This approach will allow the potential risk of cancer in individuals occupationally exposed to PAHs to be assessed better.

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.

The toxicokinetics of pyrene and its metabolites in rats

Five experiments were conducted in male Sprague-Dawley rats regarding the kinetic of urinary excretion of 1-hydroxypyrene (1-OHP) following i.v., oral and dermal exposure to 0.5-50 micromol/kg pyrene either as a single substance or as mixture of various polycyclic aromatic hydrocarbons (PAH). Frequent urine collections over 48 h after exposure and a tissue versus time distribution experiment using [14C]pyrene allowed to define the kinetic profile of both pyrene and 1-OHP. For all exposure routes, there is a linear relationship over two orders of magnitude between the dose of pyrene and the urinary excretion of 1-OHP. Differences in biliary/urinary 1-OHP excretion ratio in canulated rats (3) versus faecal/urinary 1-OHP excretion ratio in non-canulated rats (0.6) indicate major enterohepatic recirculation of the metabolite. Half-lives of both pyrene and 1-OHP in all measured tissues were all comprised between 3.1 and 5.4 h, and 5.2-6.7 h, respectively, so that no long term accumulation would be predicted from these values for any tissue. Binary and ternary mixtures involving naphthalene and benzo(a)pyrene in addition to pyrene has no influence on the urinary excretion profile of 1-OHP. All these observations led to the proposal of a dynamic compartment model of pyrene and metabolite flows indicating that following rapid initial distribution to fatty tissues, pyrene is rapidly biotransformed into various metabolites and undergoes major enterohepatic recycling. Part of the initially formed and part of the recirculated 1-OHP eventually undergoes urinary excretion such that close to 60% of pyrene is eliminated as metabolites in urine by 24 h after injection while 20% is excreted in the faeces over the same period.

A toxicokinetic study to elucidate 3-hydroxybenzo(a)pyrene atypical urinary excretion profile following intravenous injection of benzo(a)pyrene in rats.

The toxicokinetics of benzo(a)pyrene (BaP) and 3‐hydroxybenzo(a)pyrene (3‐OHBaP) were assessed in 36 male Sprague–Dawley rats injected intravenously with 40 µmol kg1 of BaP to explain the reported atypical urinary excretion profile of 3‐OHBaP. Blood, liver, kidney, lung, adipose tissue, skin, urine and feces were collected at t = 2, 4, 8, 16, 24, 33, 48, 72 h post‐dosing. BaP and 3‐OHBaP were measured by high‐performance liquid chromatography/fluorescence. A biexponential elimination of BaP was observed in blood, liver, skin and kidney (t½ of 4.2–6.1 h and 12.3–14.9 h for initial and terminal phases, respectively), while a monoexponential elimination was found in adipose tissue and lung (t½ of 31.2 and 31.5 h, respectively). A biexponential elimination of 3‐OHBaP was apparent in blood, liver and skin (t½ of 7.3–11.7 h and 15.6–17.8 h for initial and terminal phases, respectively), contrary to adipose tissue, lung and kidney. In adipose tissue and lung, a monophasic elimination of 3‐OHBaP was observed (t½ of 27.0 h and 24.1 h, respectively). In kidney, 3‐OHBaP kinetics showed a distinct pattern with an initial buildup during the first 8 h post‐dosing followed by a gradual elimination (t½ of 15.6 h). In the 72‐h post‐treatment, 0.21 ± 0.09% (mean ± SD) of dose was excreted as 3‐OHBaP in urine and 12.9 ± 1.0% in feces while total BaP in feces represented 0.40 ± 0.16% of dose. This study allowed the identification of the kidney as a retention compartment governing 3‐OHBaP atypical urinary excretion. Copyright

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.

Biological monitoring of exposure to mixtures.

This short review is aimed at establishing general principles of biological monitoring for chemical mixtures. When interactions occur, they appear to be toxicokinetic in nature, often resulting from competition between two or more substances for the same biotransformation enzymes. A threshold is frequently observed for such an interaction, so that it might not influence the relationship between the absorbed dose and the value of the relevant biomarker. The extent of the interaction between pairs of chemicals also depends on the extent of biotransformation of each compound. As a result, the measurement of the parent compound or its metabolite will be differentially influenced by the presence of an interfering chemical. Biological limit values (BLV) are often established from the correlation between the bioindicator concentration in a given biological medium and the airborne concentration of the parent compound. When this relationship is derived from exposure to pure chemicals, it might not always yield an appropriate BLV for monitoring exposure to a mixture that includes this particular chemical. Under certain conditions such as the stability of mixture composition, a single biomarker such as 1-hydroxypyrene in PAH exposure can be used to reflect the overall exposure to a mixture. Finally, there is clearly a need for a greater research effort on the toxicology of mixtures to make biological monitoring a useful tool in occupational health.