Considering the cumulative risk of mixtures of chemicals – A challenge for policy makers

Background

The current paradigm for the assessment of the health risk of chemical substances focuses primarily on the effects of individual substances for determining the doses of toxicological concern in order to inform appropriately the regulatory process. These policy instruments place varying requirements on health and safety data of chemicals in the environment. REACH focuses on safety of individual substances; yet all the other facets of public health policy that relate to chemical stressors put emphasis on the effects of combined exposure to mixtures of chemical and physical agents. This emphasis brings about methodological problems linked to the complexity of the respective exposure pathways; the effect (more complex than simple additivity) of mixtures (the so-called 'cocktail effect'); dose extrapolation, i.e. the extrapolation of the validity of dose-response data to dose ranges that extend beyond the levels used for the derivation of the original dose-response relationship; the integrated use of toxicity data across species (including human clinical, epidemiological and biomonitoring data); and variation in inter-individual susceptibility associated with both genetic and environmental factors.

Methods

In this paper we give an overview of the main methodologies available today to estimate the human health risk of environmental chemical mixtures, ranging from dose addition to independent action, and from ignoring interactions among the mixture constituents to modelling their biological fate taking into account the biochemical interactions affecting both internal exposure and the toxic potency of the mixture.

Results

We discuss their applicability, possible options available to policy makers and the difficulties and potential pitfalls in implementing these methodologies in the frame of the currently existing policy framework in the European Union. Finally, we suggest a pragmatic solution for policy/regulatory action that would facilitate the evaluation of the health effects of chemical mixtures in the environment and consumer products.

Conclusions

One universally applicable methodology does not yet exist. Therefore, a pragmatic, tiered approach to regulatory risk assessment of chemical mixtures is suggested, encompassing (a) the use of dose addition to calculate a hazard index that takes into account interactions among mixture components; and (b) the use of the connectivity approach in data-rich situations to integrate mechanistic knowledge at different scales of biological organization.

     

A retrospective analysis of nickel exposure data at a South African base metal refinery

This study aimed to analyze historical soluble nickel exposure data from a South African base metal refinery and to identify trends in the soluble nickel exposure from 1981 until 2014 in the electrowinning department.

Exposure data were presented in an exposure matrix, which described exposure profiles for both area and personal exposures inside two tankhouses. Exposure data were standardized by converting total nickel aerosol concentrations to inhalable nickel concentrations (correction factor 3.0). One-way analyses of variances (ANOVA) were conducted to identify significant differences in log-transformed area and personal exposures from 1982 until 2014, and the trends were assessed with linear regression. Differences were evaluated in area exposure between sections inside the tankhouses, i.e., East, West, and Center bays and in personal exposure between occupations, i.e., cell workers, crane drivers, and supervisors.

Area exposure in Tankhouse 1 declined significantly (p ≤ 0.0001) between 1982 and 1986 with a factor of 29. However, after 1986 no significant downward trend in area exposure was evident in Tankhouse 1. Personal exposures in Tankhouse 1 significantly (p ≤ 0.0001) decreased with a factor of three between 1991 and 2014. No significant trends were evident in area and personal exposure in Tankhouse 2.

Downward exposure trends were evident in Tankhouse 1 and may be ascribed to the implementation of various control measures and process changes, e.g., increasing polypropylene bead load. Limited data were available for Tankhouse 2, therefore, no trend in exposure could be established. Retrospective analyses may be used to identify trends and anomalies in exposure which might not have been identified during daily exposure monitoring.     

Sicherheitsfaktoren in der Risikobewertung von Chemikalien

Risk assessment of chemicals is based on data from experimental exposure of animals. Departing from the dose/concentration at which no toxic effects have been observed in animals (no observed adverse effect level, NOAEL), the dose/exposure in humans that will not result in toxic effects is derived by extrapolation done in two steps.Step one is the extrapolation from animal to man and, traditionally, a safety factor of 10 is used to account for differences in toxicokinetics and in toxicodynamics.Likewise, a safety factor of 10 is used in step two, which takes differences into account between the “median” human and the whole population including the sensitive subpopulation.There is increasing awareness that substance-specific factors should be used if data exist.Some regulators apply additional factors to account for uncertainty in the data and model uncertainties. The concept of safety factors is used to derive “safe” levels of exposure or “safe” doses.Application of the margin of safety (MOS) approach is different in which the distance is evaluated between a relevant level of toxicity (NOAEL) in animals and the level of exposure in humans.This approach is used when,e.g., food contamination with levels higher than safe levels have been found.The MOS approach is also used in chemical risk assessment. As the public often does not understand the assumptions behind safe levels, lay people associate levels higher than the safe levels with acute health risks.     

Combining PM2.5 Component Data from Multiple Sources: Data Consistency and Characteristics Relevant to Epidemiological Analyses of Predicted Long-Term Exposures

Background

Regulatory monitoring data have been the exposure data resource most commonly applied to studies of the association between long-term PM_2.5 components and health. However, data collected for regulatory purposes may not be compatible with epidemiological studies.

Objectives

We studied three important features of the PM_2.5 component monitoring data to determine whether it would be appropriate to combine all available data from multiple sources for developing spatiotemporal prediction models in the National Particle Component and Toxicity (NPACT) study.

Methods

The NPACT monitoring data were collected in an extensive monitoring campaign targeting cohort participant residences. The regulatory monitoring data were obtained from the Chemical Speciation Network (CSN) and the Interagency Monitoring of Protected Visual Environments (IMPROVE). We performed exploratory analyses to examine features that could affect our approach to combining data: comprehensiveness of spatial coverage, comparability of analysis methods, and consistency in sampling protocols. In addition, we considered the viability of developing spatiotemporal prediction models given a) all available data, b) NPACT data only, and c) NPACT data with temporal trends estimated from other pollutants.

Results

The number of CSN/IMPROVE monitors was limited in all study areas. The different laboratory analysis methods and sampling protocols resulted in incompatible measurements between networks. Given these features we determined that it was preferable to develop our spatiotemporal models using only the NPACT data and under simplifying assumptions.

Conclusions

Investigators conducting epidemiological studies of long-term PM_2.5 components need to be mindful of the features of the monitoring data and incorporate this understanding into the design of their monitoring campaigns and the development of their exposure prediction models.

Citation

Kim SY, Sheppard L, Larson TV, Kaufman JD, Vedal S. 2015. Combining PM_2.5 component data from multiple sources: data consistency and characteristics relevant to epidemiological analyses of predicted long-term exposures. Environ Health Perspect 123:651–658; http://dx.doi.org/10.1289/ehp.1307744     

Sex Differences in Urinary Levels of Several Biological Indicators of Exposure: A Simulation Study Using a Compartmental-Based Toxicokinetic Model

Toxicokinetic modeling is a useful tool to describe or predict the behavior of a chemical agent in the human or animal organism. A general model based on four compartments was developed in a previous study to quantify the effect of human variability on a wide range of biological exposure indicators.

The aim of this study was to adapt this existing general toxicokinetic model to three organic solvents—methyl ethyl ketone, 1-methoxy-2-propanol, and 1,1,1,-trichloroethane—and to take into account sex differences. In a previous human volunteer study we assessed the impact of sex on different biomarkers of exposure corresponding to the three organic solvents mentioned above. Results from that study suggested that not only physiological differences between men and women but also differences due to sex hormones levels could influence the toxicokinetics of the solvents. In fact the use of hormonal contraceptive had an effect on the urinary levels of several biomarkers, suggesting that exogenous sex hormones could influence CYP2E1 enzyme activity. These experimental data were used to calibrate the toxicokinetic models developed in this study.

Our results showed that it was possible to use an existing general toxicokinetic model for other compounds. In fact, most of the simulation results showed good agreement with the experimental data obtained for the studied solvents, with a percentage of model predictions that lies within the 95% confidence interval varying from 44.4 to 90%. Results pointed out that for same exposure conditions, men and women can show important differences in urinary levels of biological indicators of exposure. Moreover, when running the models by simulating industrial working conditions, these differences could be even more pronounced.

A general and simple toxicokinetic model, adapted for three well-known organic solvents, allowed us to show that metabolic parameters can have an important impact on the urinary levels of the corresponding biomarkers. These observations give evidence of an interindividual variability, an aspect that should have its place in the approaches for setting limits of occupational exposure.     

A comparison of control banding tools for nanomaterials

Control banding (CB) is a useful approach to evaluate and control the risk of exposure to nanomaterials (NM) due to uncertainty surrounding their toxicity and challenges associated with their measurement. Four CB tools specifically developed for NMs (NanoSafer, Stoffenmanager-Nano, NanoTool, and the Precautionary matrix) have been evaluated for their changes to differences in hazard and exposure input data. The hazard and exposure classification were also compared with experimental data. The tools provided different hazard and emission/exposure outputs when compared with each other and with experimental data.

For some of the tools the information required to estimate the hazard is not always available in the Safety Data Sheet and it requires expert judgement. The tools have the potential to be valuable starting points to assess areas of high priority, although outputs should be interpreted with care. Further work should be done to improve their estimates, especially the inclusion of modifiers that account for the effectiveness of the ventilation and the effect of high temperatures during the process.     

Occupational health and safety in cannabis production: an Australian perspective

The legal Australian cannabis industry has been rapidly expanding due to increased awareness of the plant’s therapeutic potential, as well its diverse range of applications including biofuel, textiles, building materials, food, nutritional supplement, and animal feed. The objective of this paper is to describe the current landscape of the commercial Australian cannabis industry, summarise occupational health and safety (OHS) hazards in cannabis-related working environments, and provide suggestions for safeguarding worker health and well-being in this emerging industry.

A comprehensive search of peer-reviewed and grey literature published between 1900 and 2017 was undertaken to identify case studies and original epidemiological research on OHS hazards associated with the cannabis cultivation and the manufacture of cannabis-based products. The review found that the majority of OHS studies were undertaken in the hemp textile industry during the late twentieth century, with a small number of articles published from a variety of occupational environments including forensic laboratories and recreational marijuana farms. Cannabis harvesting and initial processing is labour intensive, and presents a physical hazard Depending on the operation, workers may also be exposed to a variety of biological, chemical, and physical hazards including: organic dusts, bioaerosols, pollen/allergens, volatile organic compounds, psychoactive substances (tetrahydrocannabinol [THC])), noise, and ultraviolet radiation.

Little research has been undertaken on the exposure to inhalable organic dust and other bioaerosols during the commercial cultivation and manufacture of cannabis-based products. Furthermore, there is an absence of Australian-based research and OHS guidance materials to help professionals develop risk management strategies in this evolving industry.

It is recommended that:

• Investigation into the toxicological properties of cannabis dusts, specifically in relation to potential occupational exposures during cultivation and manufacture, should be a priority.

• The interim adoption of the respirable cotton dust exposure standard of 0.2 mg/m³ for workplace exposure in hemp facilities until a cannabis workplace exposure standard is developed, and that exposure to medicinal cannabis containing THC are kept as low as reasonably practicable.

• An industry partnership be established for the development of an Australian health and safety guideline for the production of medicinal cannabis and hemp.

• A classification to meet the requirements of the Global Harmonization Scheme should be undertaken to ensure consistency in the use of safety and risk phrases in cannabis-related industries.

     

Calculation of a safety factor in setting health based permissible levels for occupational exposure

Summary The proposed procedure for extrapolation from animal data to permissible levels for occupational exposure has been put to the test for 11 compounds. The proposed procedure does not seem to offer less protection than the published permissible levels, which to a large extent were also based upon human data. In about half the cases the extrapolated levels offer even more protection than the levels established in Western countries. The proposed procedure may be regarded as a useful tool in evaluation of health risk in occupational exposure, in the case that new non-carcinogenic agents are introduced in industry, particularly if more adequate animal toxicity data come available.     

Long-term mercury excretion in urine after removal of amalgam fillings

The long-term urinary mercury excretion was determined in 17 28- to 55-year-old persons before and at varying times (up to 14 months) after removal of all (4–24) dental amalgam fillings. Before removal the urinary mercury excretion correlated with the number of amalgam fillings. In the immediate post-removal phase (up to 6 days after removal) a mean increase of 30% was observed. Within 12 months the geometric mean of the mercury excretion was reduced by a factor of 5 from 1.44 g/g (range: 0.57–4.38 g/g) to 0.36 g/g (range: 0.13–0.88 g/g). After cessation of exposure to dental amalgam the mean half-life was 95 days. These results show that the release of mercury from dental amalgam contributes predominantly to the mercury exposure of non-occupationally exposed persons. The exposure from amalgam fillings thus exceeds the exposure from food, air and beverages. Within 12 months after removal of all amalgam fillings the participants showed substantially lower urinary mercury levels which were comparable to those found in subjects who have never had dental amalgam fillings. A relationship between the urinary mercury excretion and adverse effects was not found. Differences in the frequency of effects between the pre- and the post-removal phase were not observed.     

Time extrapolation and interspecies extrapolation for locally acting substances in case of limited toxicological data

In the case of substances with a limited toxicological data base there is often (i) a lack of qualified human toxicological data; and (ii) a paucity of studies with adequate exposure duration. Hence, several extrapolations have to be performed to arrive at appropriate risk assessments or derive occupational exposure limits. The present paper deals with the possibilities for extrapolating the change in effect concentrations over time (time extrapolation, e.g. from subacute to chronic exposure) and for interspecies extrapolation (from animal to human) in connection with locally acting substances (respiratory toxicants). To justify the time extrapolation factors, 46 technical reports produced by the US National Toxicology Program (NTP) involving studies with subacute, subchronic and chronic exposure duration were evaluated. On the basis of geometric mean values, decreases in effect concentrations by factors of 3.2 (subacute --> subchronic), 2.7 (subchronic --> chronic) and 6.6 (subacute --> chronic) were found. Differentiation according to animal species (mouse, rat), sex or substance properties did not result in any relevant changes of the mean value. NTP studies with less than lifetime exposure periods (subacute, subchronic) in many cases showed different locations of respiratory effects compared with chronic studies, and thus offered limited possibilities for qualitative prediction of long-term respiratory effects (occurrence of effects in certain regions of the respiratory tract). With regard to interspecies extrapolation, gaseous and particulate substances were evaluated separately. With some modifications (e.g. consideration of the clearance of particles of low solubility), the 1994 US Environmental Protection Agency (EPA) model for deriving reference concentrations for humans on the basis of experimental data in animals is proposed for inhalable particulate substances. In the case of gaseous substances, the assumptions of the EPA model do not seem to consider sufficiently the local inhomogeneity in substance distribution and anatomical and histological differences between the upper respiratory tracts of rodents and humans. Considerable uncertainty would attach to a default factor for interspecies extrapolation for gaseous substances.     

Can observations of workplace bullying really make you depressed? A response to Emdad et al.

Background

A recent study by Emdad and colleagues published in International Archives of Occupational and Environmental Health concluded that being a bystander to workplace bullying is related to future symptoms of depression. In this response to the authors, we argue, through the use of empirical evidence, that this relationship can be explained by the observers own exposure to bullying. Furthermore, by also investigating the reversed association between the variables, we show that observations of workplace bullying can be influenced by symptoms of psychological distress.

Method

A reanalysis of prospective questionnaire survey data with a two-year time lag based on a representative sample of Norwegian employees was used to determine long-term relationships between observed bullying, self-reported exposure to bullying, and psychological distress.

Results

Bivariate, baseline observations of others being bullied were significantly associated with subsequent symptoms of psychological distress. Yet, this association disappeared when controlling for the observers own exposure to bullying. Analyzing reversed relationship between the variables, baseline symptoms of distress predicted being a bystander at follow-up.

Conclusion

By showing that the relationship between being a bystander to bullying and distress can be fully explained by the observers own exposure to bullying, our results question the conclusion by Emdad et al. (Int Arch Occup Environ Health. doi:10.1007/s00420-012-0813-1, 2012) that observed bullying in itself is related to subsequent distress. Together with the finding that psychological distress predicts subsequent observations of bullying, it is concluded that future research on observers should always take the observers’ own exposure to bullying, as well as negative perceptions biases, into account.     

Health effects of swimmers and nonpoint sources of contaminated water

Microbiological contamination from nonpoint sources of pollution is usually related to animal faecal wastes through urban, pastureland and forest run‐off of stormwater. Currently‐used bacterial water quality indicators cannot discriminate between human and animal faecal contamination and, therefore, it is common practice to treat the risk associated with exposure to water polluted by animal or human wastes as equally hazardous. The purpose of this study was to determine if there is a risk of gastrointestinal illness after a swimming exposure to water contaminated with animal faecal wastes.

The health status and swimming activity of volunteer study participants was followed for 49 days during June, July and August. Multiple bacterial indicators of water quality were monitored daily during the course of the study.

Swimming‐associated symptomatic gastrointestinal illness was observed in individuals who swam in animal nonpoint source contaminated water. Swimmer illness was not associated with high densities of common faecal indicator bacteria or high volume rainy days. Swimmer illness was associated with high numbers of swimmers per day and high densities of staphylococci. The observed illnesses appeared to be caused by a swimmer to swimmer transmission via the water.     

The influence of contaminant and water quality conditions on larval striped bass in the Potomac River and upper Chesapeake Bay in 1990: Anin situ study

In situ contaminant and water quality studies were conducted with striped bass prolarvae,Morone saxatilis, in two major spawning areas of the Chesapeake Bay in 1990 to explore the possible effects of water quality and contaminants conditions on survival. Three 96-hin situ survival studies with striped bass prolarvae were conducted at three stations in the Potomac River and three stations in the upper Chesapeake Bay during a major portion of the spawning season (13–20°C). Water quality parameters, inorganic contaminants and organic contaminants were monitored in the water column at these three stations during the experiments. Concentrations of 10 metals associated with precipitation events occurring at field sites on the Potomac River and upper Chesapeake Bay were also determined.Survival of prolarvae ranged from 2 to 17.5% in all three 96-h tests conducted in the Potomac River. Control survival was greater than 79%. Survival of prolarvae during experiment 3 (all stations combined for each experiment) was significantly lower than survival of prolarvae during experiment 1. The low survival of prolarvae during experiment 3 occurred concurrently with a reported fish kill on the Potomac River. Chromium (14 g/L) and zinc (119 g/L) concentrations exceeding U.S. EPA water quality criteria were reported from a 48-h composite sample taken during experiment 3. Lower than normal pH conditions (6.8 and 6.9) were also documented during this experiment. Arsenic, chromium, and zinc may have been stressful.Survival of prolarvae at the three stations during upper Chesapeake Bay tests ranged from 36 to 52.5% for 96-h exposures but was slightly lower (23–34.5%) during a 120-h exposure. Control survival was >81% in all experiments. Survival of prolarvae during all experiments in the upper Bay was similar to natural survival that occurs with this life stage. Adverse water quality and contaminant conditions were not reported in the upper Chesapeake Bay striped bass spawning area.Detectable concentrations of cadmium (0.80 and 0.89 g/L), aluminum (5.4 g/L), chromium (1.1 g/L), and zinc (2.5 g/L) were reported in acidic precipitation samples (pH 3.4) collected from the Potomac River site. Surface water concentrations of these metals did not increase in the Potomac River study area after the precipitation events. The following metals were detected in acidic precipitation (pH 4.06–5.12) in the upper Chesapeake Bay: 22.1 g/L Al; 1.1, 1.8, 2.3 g/L Cd; 1.2 g/L Cu; 2.7 and 3.1 g/L Pb and 4.6 g/L Zn. Concentrations of Al (22.1 g/L) and Pb (3.1 g/L) in precipitation corresponded with increased concentrations in the surface waters at a nearby station in the upper Chesapeake Bay study area.     

Biological exposure limit for occupational exposure to coal tar pitch volatiles at cokeovens

Summary Biological monitoring is an efficient tool in the evaluation of exposure to chemical agents. However, the dose-response of adverse health effects using biological exposure indices and biological limit values are rarely available. This paper presents an estimation of the occupational exposure limit value of 1-hydroxypyrene in urine, a biological exposure indicator of polycyclic aromatic hydrocarbons (PAH). A large-scale study of the exposure of cokeoven workers to PAH, in wich both air sampling (benzene soluble matter and individual PAH including benzo()pyrene) and biological monitoring (1-hydroxypyrene in urine) were applied, made it possible to establish an empirical mathematical relationship between the air sampling data and biological monitoring data. It was calculated that cokeoven workers with a urinary concentration of 1-hydroxypyrene of 2.3 mol/mol creatinine after a 3-day working period equals the airborne threshold limit value (TLV) of coal tar pitch volatiles (CTPV). Epidemiological studies have quantified the relative risk of lung cancer for topside and non-topside cokeoven workers. The published environmental exposure data of topside and non-topside cokeoven workers were used to determine the time-average exposure. The data of 1-hydroxypyrene in the urine of cokeoven workers and data of epidemiological studies from different coke plants were combined according to the concentrations of PAH in the air. Thus, it was possible to establish an indirect relationship between lung cancer mortality risk and the biological exposure indicator for cokeoven workers. Exposure at the level of the suggested tentative biological exposure limit (BEL) of 2.3 mol/ mol creatinine is estimated to be equal to a relative risk of lung cancer of approximately 1.3.     

The Prime Diabetes Model: Novel Methods for Estimating Long-Term Clinical and Cost Outcomes in Type 1 Diabetes Mellitus

Background

Recent publications describing long-term follow-up from landmark trials and diabetes registries represent an opportunity to revisit modeling options in type 1 diabetes mellitus (T1DM).

Occupational asthma risk from exposures to toluene diisocyanate: A review and risk assessment

Background

Toluene Diisocyanate (TDI) is a known respiratory sensitizer linked to occupational asthma (OA). To better manage worker risks, an appropriate characterization of the TDI‐OA dose‐risk relationship is needed.

Methods

The literature was reviewed for data suitable for dose‐response modeling. Previous study data were fit to models to derive prospective occupational exposure limits (OELs), using benchmark dose (BMD) and low‐dose extrapolation approaches.

Results

Data on eight TDI‐exposed populations were suitable for analysis. There were 118 OA cases in a population contributing 13 590 person‐years. The BMD‐based OEL was 0.4 ppb. The OEL based on low‐dose extrapolation to working lifetime extra risk of 1/1000 was 0.3 ppb.

Conclusions

This study synthesized epidemiologic data to characterize the TDI‐OA dose‐risk relationship. This approach yielded prospective OEL estimates below recent recommendations by the American Conference of Governmental Industrial Hygienists, but given significant study limitations, this should be interpreted with caution. Confirmatory research is needed.

     

In Utero Exposure to Bisphenol A Shifts the Window of Susceptibility for Mammary Carcinogenesis in the Rat

Background

Bisphenol A (BPA) is a ubiquitous environmental chemical with reported endocrine-disrupting properties.

Objective

Our goal in this study was to determine whether prenatal exposure to BPA predisposes the adult rat mammary gland to carcinogenesis.

Methods

Pregnant rats were treated orally with 0, 25, or 250 μg BPA/kg body weight (BW) from gestation day (GD) 10 to GD21. For tumorigenesis experiments, prenatally exposed female offspring received a single gavage of 7,12-dimethylbenz(a)anthracene (DMBA; 30 mg/kg BW) on postnatal day (PND) 50, or PND100.

Results

Prenatal exposure of the dam to 250 μg BPA/kg BW combined with a single exposure of female offspring to DMBA on PND100, but not on PND50, significantly increased tumor incidence while decreasing tumor latency compared with the control group. Prenatal exposure of the dam to 250 μg BPA/kg BW, in the absence of DMBA to the female offspring, increased cell proliferation and elicited differential effects at the protein level at PND100 compared with PND50. Differentially regulated proteins in the mammary gland included estrogen receptor-α, progesterone receptor-A, Bcl-2, steroid receptor coactivators, epidermal growth factor receptor, phospho-insulin-like growth factor 1 receptor, and phospho-Raf.

Conclusions

Our study demonstrates that oral prenatal exposure to BPA increases mammary cancer susceptibility in offspring and shifts the window of susceptibility for DMBA-induced tumorigenesis in the rat mammary gland from PND50 to PND100. These changes are accompanied by differential effects of prenatal BPA exposure on the expression of key proteins involved in cell proliferation.     

Comprehensive analysis of the use of pre-procedure ultrasound for first- and second-trimester abortion

Background

The use of ultrasound (US) is common in some settings before an abortion procedure. However, its positive effect on the safety or efficacy (ability to complete abortion) of the procedure has not been established. Our aim was to determine whether the use of pre-procedure US improves safety and/or efficacy of the abortion procedure.

Methods

We searched the following databases: Pubmed, Embase, Lilacs and Popline; reference lists of retrieved papers; and Google. We considered any controlled trial comparing women seeking abortion who received pre-procedure US to those who did not. Our outcome measures were efficacy of the abortion, complication rates and side effects.

Results

We did not identify any controlled trials or systematic reviews comparing the use of pre-procedure US to no US prior to abortion.

Conclusions

Ultrasound is widely used in pregnancy to estimate gestational age and to detect any abnormalities of the pregnancy or uterus. The effect of its use among women undergoing abortion is unclear, and only indirect evidence is available.     

Biomonitoring of 4,4′-methylene dianiline by measurement in hydrolysed urine and plasma after epicutaneous exposure in humans

Five healthy volunteers were dermally exposed for 1 h to 0.75–2.25 mol 4,4-methylene dianiline (MDA) dissolved in isopropanol, by use of a patchtest technique. Determination of MDA remaining in the patch units after exposure showed that a median of 28% (range 25–29%) was absorbed. By analysis of hydrolysed plasma, an initial accumulation of MDA could be shown, and then a decline. MDA was also detected in hydrolysed urine. The maximum rate of MDA excretion in urine was found 6–11 h after the onset of exposure. Within two subjects studied at three doses, the urinary excretion was proportional to the exposure. The elimination half-lives (elim-t _1/2) in plasma and urine had medians of 13 and 7 h, respectively. In eight out of nine exposures, the elim-t _1/2 was longer in plasma than in urine. Slow acetylation seemed to be associated with short elim-t _1/2 in urine. The median of total MDA amount excreted in urine during 48 h, was 33 nmol for the five subjects exposed to 0.75 mol, which corresponded to roughly 16% (range 2%–26%) of the absorbed dose while only a limited number of individuals were studied, the data still indicated that MDA in hydrolysed plasma or urine can be used for biological monitoring of occupational dermal exposure. However, the individual variation must be taken into account. Sampling should preferably be made several hours post shift. Urine is preferred before plasma at low exposures, because of its higher concentrations of MDA.     

Cancer risk assessment for health care workers occupationally exposed to cyclophosphamide

In the present study a cancer risk assessment of occupational exposure to cyclophosphamide (CP), a genotoxic carcinogenic antineoplastic agent, was carried out following two approaches based on (1) data from an animal study and (2) data on primary and secondary tumors in CP-treated patients. Data on the urinary excretion of CP in health care workers were used to estimate the uptake of CP, which ranged from 3.6 to 18 g/day. Based on data from an animal study, cancer risks were calculated for a health care worker with a body weight of 70 kg and a working period of 40 years, 200 days a year (linear extrapolation). The lifetime risks (70 years) of urinary bladder cancer in men and leukemias in men and women were found to be nearly the same and ranged from 95 to 600 per million. Based on the patient studies, cancer risks were calculated by multiplication of the 10-year cumulative incidence per gram of CP in patients by the estimated mean total uptake in health care workers over 10 years, 200 days a year. The risk of leukemias in women over 10 years ranged from 17 to 100 per million using the secondary tumor data (linear extrapolation). Comparable results were obtained for the risk of urinary bladder tumors and leukemias in men and women when primary tumor data were used. Thus, on an annual basis, cancer risks obtained from both the animal and the patient study were nearly the same and ranged from about 1.4 to 10 per million. In The Netherlands it is proposed that, for workers, a cancer risk per compound of one extra cancer case per million a year should be striven for (target risk) and that no risk higher than 100 per million a year (prohibitory risk) should be tolerated. From the animal and the patient study it appears that the target risk is exceeded but that the risk is still below the prohibitory risk.