Monitoring the effects of atmospheric ethylene near polyethylene manufacturing plants with two sensitive plant species.

Data of a multi-year (1977-1983) biomonitoring programme with marigold and petunia around polyethylene manufacturing plants was analysed to assess plant responses to atmospheric ethylene and to determine the area at risk for the phytotoxic effects of this pollutant. In both species, flower formation and growth were severely reduced close to the emission sources and plant performance improved with increasing distance. Plants exposed near the border of the research area had more flowers than the unexposed control while their growth was normal. Measurements of ethylene concentrations at a border site revealed that the growing season mean was 61.5 g m(-3) in 1982 and 15.6 g m(-3) in 1983. In terms of number of flowers, petunia was more sensitive than marigold and adverse effects were observed within ca. 400 m distance from the sources for marigold and within ca. 460 m for petunia. The area at risk (ca. 870 m) for ethylene-induced growth reduction was also limited to the industrial zone. Plants were more sensitive to ethylene in terms of growth reduction than in terms of inhibition of flowering. In the Netherlands, maximum permissible levels of ethylene are currently based on information from laboratory and greenhouse studies. Our results indicate that these levels are rather conservative in protecting field-grown plants against ethylene-induced injury near polyethylene manufacturing plants.

Monitoring, modelling and environmental exposure assessment of industrial chemicals in the aquatic environment.

Monitoring and laboratory data play integral roles alongside fate and exposure models in comprehensive risk assessments. The principle in the European Union Technical Guidance Documents for risk assessment is that measured data may take precedence over model results but only after they are judged to be of adequate reliability and to be representative of the particular environmental compartments to which they are applied. In practice, laboratory and field data are used to provide parameters for the models, while monitoring data are used to validate the models' predictions. Thus, comprehensive risk assessments require the integration of laboratory and monitoring data with the model predictions. However, this interplay is often overlooked. Discrepancies between the results of models and monitoring should be investigated in terms of the representativeness of both. Certainly, in the context of the EU risk assessment of existing chemicals, the specific requirements for monitoring data have not been adequately addressed. The resources required for environmental monitoring, both in terms of manpower and equipment, can be very significant. The design of monitoring programmes to optimise the use of resources and the use of models as a cost-effective alternative are increasing in importance. Generic considerations and criteria for the design of new monitoring programmes to generate representative quality data for the aquatic compartment are outlined and the criteria for the use of existing data are discussed. In particular, there is a need to improve the accessibility to data sets, to standardise the data sets, to promote communication and harmonisation of programmes and to incorporate the flexibility to change monitoring protocols to amend the chemicals under investigation in line with changing needs and priorities.

Kaplan-Meier tumor probability as a starting point for dose-response modeling provides accurate lifetime risk estimates from rodent carcinogenicity studies.

In rodent carcinogenicity studies the linearized multistage model for modelling the dose-response for specific tumor incidence has limitations in accuracy. This note provides an alternative basic method for analyzing the dose-response relationship. It is based on an actuarial analysis of mortality and specific tumor incidence. The survival and the Kaplan-Meier specific tumor probability are fitted to a Weibull model, in which exposure level, exposure period, and observation period are independent variables. The mortality from specific cancers at a certain time is simulated by means of the product of survival and specific tumor rate (derivative of Kaplan-Meier tumor probability) as function of exposure level, exposure duration, and observation period, integrated over the observation period. The model is demonstrated by means of fitting the mortality and tumor incidence data from the second NTP mice study on butadiene to a Weibull model and to the linear, so-called, one-hit model. It will be shown that, in the experimental exposure range, the Weibull model is far superior to the one-hit model and predicts the specific tumor incidence with a high accuracy over the total dose range. The Kaplan-Meier probability model for a specific tumor is also useful for regulatory risk estimation. It is proposed that to develop a specific tumor a risk level of 1 in 1,000 over a lifetime is about equal to 5 in 10,000 at 50% survival of the population. The Kaplan-Meier probability may be estimated at the time of 50% survival of the exposed population, which can be deduced from the all mortality data. This estimation method provides meaningful data, using exposure level, exposure duration, and observation period properly. The advantage of the actuarial analysis method for interpreting rodent studies is that allowance is made for competition between death causes, which is essential in case of considerable difference in mortality and specific mortality between dose groups. Integrating the product of survival and specific tumor rate is the proper way to predict, comparatively, mortality and specific mortality in exposed and unexposed rodent populations.

Mortality update of workers exposed to acrylonitrile in The Netherlands.

A retrospective cohort study investigating the cause-specific mortality patterns of 2842 workers occupationally exposed to acrylonitrile for at least 6 months before 1 July 1979 was updated. The comparison group consisted of 3961 workers from a nitrogen fixation plant during the same time interval. Industrial hygiene assessments quantified past exposure to acrylonitrile, the use of personal protective equipment, and exposure to other potential carcinogenic agents. All 6803 workers were followed for mortality until 1 January 1996. The follow-up was almost complete (99.6%), and for 99.3% the cause of death was ascertained. Age distribution, follow-up period, and temporal changes in background mortality rates were adjusted for in calculations of standardized mortality ratios for separate causes of death. Cumulative dose-effect relations were determined for 3 exposure categories and 3 latency periods. The results showed that, although cancer mortality fluctuated slightly, no cancer excess seems related to exposure to acrylonitrile.

Estimating skin permeation. The validation of five mathematical skin permeation models.

This study provides an analysis of the reliability of five mathematical models, simulating permeation of substances through the skin from aqueous solutions. An extensive database was generated, containing data on 123 measured permeation coefficients of 99 different chemicals and their physicochemical properties. In addition, in this database all relevant experimental conditions are included. The coefficients of the different skin permeation models were estimated by non-linear multiple regression, using the octanol-water partition coefficient and the molecular weight as independent parameters. The reliability of the models was evaluated by testing variation of regression coefficients and of residual variance for subsets of data, randomly selected from the complete database. Three models were considered to provide reliable estimations of the skin permeation coefficient. These are based on the McKone and Howd model, the Guy and Potts model and the Robinson model. The last-mentioned two models were adaptations, because MW0.5 as independent parameter provided a better fit than MW (MW = molecular weight) in the original models. The McKone and Howd model and the Robinson model have the advantage, that they predict more precisely the skin permeation of highly hydrophilic and highly lipophilic chemicals compared to the Guy and Potts model. The revised Robinson model resulted always in the smallest residual variance.

Physiologically based toxicokinetic modeling of 1,3-butadiene lung metabolism in mice becomes more important at low doses.

This paper describes a physiologically based toxicokinetic model for 1,3-butadiene uptake, distribution, and metabolic clearance in mice. Model parameters for metabolic activity were estimated from the correspondence between computer simulation studies and experimental results as published in the literature. The parameterized model was validated with independent literature data. With the resulting model, the relative importance of lung metabolism as compared to metabolism in the liver increased with decreasing ambient air concentrations. This was due to saturation of metabolism in the alveolar area of the lung, which occurred in the simulations at ambient air concentrations well below current threshold limit values. At higher air concentration, liver metabolism became relatively more important. The tendency toward increased importance of lung metabolism at low doses indicates the necessity of careful extrapolation of in vivo results to low doses. Moreover, this trend may also contribute to species difference in susceptibility to the carcinogenic activity of butadiene.

Alternative acute inhalation toxicity testing by determination of the concentration-time-mortality relationship: experimental comparison with standard LC50 testing.

A new design for acute inhalation toxicity testing was evaluated and compared with results obtained according to OECD guideline 403. The new design consists of a range-finding test, which is compatible with a conventional limit test, and can be followed by determination of a concentration-time-mortality relationship, enabling calculation of LC50 (50% mortality exposure concentration) values. By exposing pairs of rats for different periods of time to about four different test concentrations in a nose-only exposure unit, LT50 (50% mortality exposure time) values were obtained for five pairs of animals per concentration. The mortality data of the approximate 20 time-concentration combinations were used to calculate the probit relationship. Estimated mortality responses from these probit relations were compared with mortality figures obtained by exposing groups of five male rats and five female rats whole-body according to conventional toxicity testing. In general, there was good correspondence between the estimated and the observed mortality response. In our hands, the determination of the concentration-time-mortality relationship takes about the same number of animals (40-50) as the conventional LC50 procedure according to the OECD guideline 403. However, the new method has several additional advantages such as: (A) LC50 values are obtained over a 10-fold range in time, with the potential of decreasing the number of animals used when regulations require acute toxicity data for different periods of exposure. (B) The obtained relationship contains considerably more valuable information for risk assessment than the LC50 value.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute inhalation toxicity study of ammonia in rats with variable exposure periods.

The acute inhalation toxicity of ammonia was examined in rats using various exposure concentrations and exposure periods. Groups of male and female rats were exposed to dynamic atmospheres containing different concentrations of ammonia for 10, 20, 40 or 60 min. The aim of the study was to establish the relationship between exposure concentration and exposure period on the one hand and mortality on the other. The correlation between exposure concentration (c), exposure period (t) and mortality rate, expressed in probits was found to be Probit = 2.30 1 n [c2.20 x t] = 47.8 The following LC50 values for ammonia were calculated: 10 min LC50 : 28,130 mg/m3 air (40,300 ppm) 20 min LC50 : 19,960 mg/m3 air (28,595 ppm) 40 min LC50 : 14,170 mg/m3 air (20,300 ppm) 60 min LC50 : 11,590 mg/m3 air (16,600 ppm).