Human reproduction and environmental risk factors

Environmental pollution is a great cause of concern, in particular, growing attention is being paid to the potential of many chemicals to affect the reproductive system in humans. The key role of prevention and control of reproductive hazards is recognized world-wide. Many chemicals have been shown to impair fertility and/or prenatal and perinatal development in experimental studies. However, a sufficient evidence of an effect on human reproduction is available for some compounds only. The use of biological markers may improve the assessment of exposure to chemicals, contribute to identify mechanisms of action and put into evidence early, reversible, biological effects. Valid biological markers are also needed in epidemiological studies: without reliable data on the level of current and past exposures it is difficult to establish a causal relationship between a pollutant and the occurrence of adverse health effects. A multidisciplinary approach to risk assessment is required. Priorities for interdisciplinary research on environmental chemicals and reproduction include the identification of susceptible population subgroups and risk assessment of exposure to multiple chemicals.     

On the rumors about the silent spring. Review of the scientific evidence linking occupational and environmental pesticide exposure to endocrine disruption health effects

Occupational exposure to some pesticides, and particularly DBCP and chlordecone, may adversely affect male fertility. However, apart from the therapeutic use of diethylstilbestrol, the threat to human reproduction posed by "endocrine disrupting" environmental contaminants has not been supported by epidemiological evidence thus far. As it concerns other endocrine effects described in experimental animals, only thyroid inhibition following occupational exposure to amitrole and mancozeb has been confirmed in humans. Cancer of the breast, endometrium, ovary, prostate, testis, and thyroid are hormone-dependent, which fostered research on the potential risk associated with occupational and environmental exposure to the so-called endocrine-disrupting pesticides. The most recent studies have ruled out the hypothesis of DDT derivatives as responsible for excess risks of cancer of the reproductive organs. Still, we cannot exclude a role for high level exposure to o,p'-DDE, particularly in post-menopausal ER+ breast cancer. On the other hand, other organochlorine pesticides and triazine herbicides require further investigation for a possible etiologic role in some hormone-dependent cancers.     

Implementation of the precautionary principle in standards for the workplace.

The objectives were to describe and discuss the current and proposed European occupational health policy on two categories of substances that pose serious effects: those potentially carcinogenic or genotoxic and those with toxic effects on reproduction. The precautionary principle was applied to setting standards for the workplace for those two categories of substances, to give an impression of the resulting limit values and the consequences of the implementation of this precautionary principle. A pragmatic approach was chosen as this starts with substantial indications of health risks. For the suspected carcinogenic or genotoxic substances 0.1 mg/m3 as a precautionary occupational exposure limit (precautionary OEL) is proposed. For the substances suspected of causing reproductive toxicity the precautionary OEL was derived in three ways, depending on the availability of data and of a current Dutch workplace standard (MAC, maximum accepted concentration): (a) by calculation based on available inhalatory animal data on the risks of reproductive toxicity; (b) by adding a safety factor of 10 to the current MAC, if no inhalatory animal data on reproductive toxicity are available; (c) by using 0.1 mg/m3 as precautionary OEL for substances suspected of having reproductive toxicity but without inhalatory animal data on reproductive toxicity and without a MAC.     

Perspectives on reproductive and developmental toxicity

Human reproduction and development is a cycle of interdependent events. Virtually all of its phases have been shown to be the primary target of one or more non-mutagenic exogenous agents. Such agents interfere with certain of the countless epigenetic or ontogenic events essential for normal completion of the cycle. Mutagens disrupt this cycle at some points, but the overwhelming majority of reproductive and developmental toxins are not mutagenic. As in all aspects of toxicology, the reproductive and developmental effects of chemicals are determined by the intrinsic nature of the chemical, the quantity of the chemical exposure, the duration of exposure and the stage of the cycle at which it occurs. Signs of reproductive toxicity range from reduced fertility to spontaneous abortion. Adverse effects on the conceptus are categorized as functional deficits, developmental retardation, structural abnormality and death. One or more of these is anticipated to occur as a result of excess exposure to most chemicals. Although the degree of hazard and risk potential can be calculated in each instance, chemicals differ markedly in their ability to interfere with reproduction (Amann, 1982) and/or development (Johnson, 1984). Standardized methods for reproductive and developmental toxicity safety evaluation are available for detecting adverse effects upon any aspect of reproduction and development. Data currently available establish that these state-of-the-art tests conducted in laboratory animals are often highly predictive of the type of adverse effect a particular chemical will have in humans, as well as the exposure level at which it will occur. By adding a modest safety factor to the no-observed-effect-level of well-executed animal studies, safe human exposure levels can be established. Responsibility for determining the intrinsic hazard potential and the risk estimate of exposure rests with manufacturers and major users of occupational and other environmental chemicals. As public awareness of reproductive and developmental hazards has increased in recent years, it has come to be understood that some chemicals have a predilection for causing reproductive impairment and/or disrupting development in the absence of other toxicity. Such substances must be identified to establish safe exposure levels and to determine the types of effects to be expected, should excessive human exposure occur. The setting of safe exposure levels is necessary both from the standpoints of ensuring public safety and avoiding product liability.     

The toxicology of 1,2-dibromo-3-chloropropane (DBCP): a brief review.

The accumulating data demonstrating the reproductive toxicity of 1, 2-dibromo-3-chloropropane (DBCP) are reviewed. The sentinel event was the discovery of infertility in male pesticide manufacturing workers. In spite of early evidence of testicular damage, first in laboratory animals and later in humans, DBCP has been widely used as a nematocide in the United States and is still used in other countries. The spermatogenic effects of DBCP are usually irreversible, and there is also evidence of toxicity to the female reproductive system. DBCP is also a CNS depressant, a liver and kidney toxin, and a skin, eye, and respiratory irritant, and is probably carcinogenic. Environmental contamination of air and water may be an additional source of exposure. Materials often used to protect workers from toxic chemicals are not being deployed for use by exposed workers, and in any case are relatively ineffective.     

Risk assessment and management of occupational exposure to pesticides in agriculture

Nearly 50% of the world labour force is employed in agriculture. Over the last 50 years, agriculture has deeply changed with a massive utilisation of pesticides and fertilisers to enhance crop protection and production, food quality and food preservation. Pesticides are also increasingly employed for public health purposes and for domestic use. Pesticide are unique chemicals as they are intrinsically toxic for several biological targets, are deliberately spread into the environment, and their toxicity has a limited species selectivity. Pesticide toxicity depends on the compound family and is generally greater for the older compounds; in humans, they are responsible for acute poisonings as well as for long term health effects, including cancer and adverse effects on reproduction. Due to their intrinsic toxicity, in most countries a specific and complex legislation prescribes a thorough risk assessment process for pesticides prior to their entrance to the market (pre-marketing risk assessment). The post-marketing risk assessment takes place during the use of pesticides and aims at assessing the risk for exposed operators. The results of the risk assessment are the base for the health surveillance of exposed workers. Occupational exposure to pesticides in agriculture concerns product distributors, mixers and loaders, applicators, bystanders, and rural workers re-entering the fields shortly after treatment. Assessing and managing the occupational health risks posed by the use of pesticides in agriculture is a complex but essential task for occupational health specialists and toxicologists. In spite of the economic and social importance of agriculture, the health protection of agricultural workforce has been overlooked for too many years, causing an heavy tribute paid in terms of avoidable diseases, human sufferance, and economic losses. Particularly in the developing countries, where agricultural work is one of the predominant job, a sustainable model of development calls for more attention to occupational risks in agriculture. The experience of many countries has shown that prevention of health risk caused by pesticides is technically feasible and economically rewarding for the individuals and the whole community. A proper risk assessment and management of pesticide use is an essential component of this preventative     

Assessment of Reproductive Risk at Work

Abstract

The risk-assessment process involves hazard identification, dose-response assessment, exposure assessment, and characterization of risk. Special competence and careful consideration are needed to assess effects on human reproduction. There is often a lack of scientific information concerning, e.g., toxic influences of chemical substances on human fertility, pregnancy, and offspring. Legislation and guidelines concerning workplace exposures need further develop men t in many countries. It is important that occupational health and safety personnel, as well as experts in this field, assist employers and employees in the development of good workplace policies for the protection of the reproductive functioning of male and female workers. A protocol for effective risk assessment is described.     

Epidemiologic input to environmental risk assessment

Epidemiological data are often rejected for risk assessment purposes because of the lack of accurate exposure data. Animal data are frequently resorted for risk assessment calculations. Such a decision should account for potential errors in animal to human risk extrapolations, which may be of 1 or 2 orders of magnitude or more. Because historical human exposure can usually be estimated with confidence that the errors would be considerably less than 1 order of magnitude, it follows that human studies should generally take precedence over animal studies, even when crude assumptions have to be made concerning human exposure levels. This paper illustrates this with cancer risk assessments for vinyl chloride and antimony, both of which relied on use of the stipulated average cohort exposure levels without use of any individual exposure data for cohort members. Linear extrapolations of risk to low exposures were used in both instances. Non-cancer risk assessments were illustrated by examining results of experimental studies of effects of ozone on ventilatory function. A simple approach, in this case involving visual inspection of study results, was again recommended. Consideration was given to concerns about synergistic effects of low-level exposure to chemical mixtures. Calculations were presented to demonstrate that estimating risks by multiplying effects of individual chemicals produces the same risk estimated by adding effects, provided that exposure levels were sufficiently low for each individual agent. It was concluded that epidemiology has much to offer to environmental health risk assessment, but that epidemiologists need to be more effective in justifying the scientific basis of the design and interpretation of epidemiological studies to laboratory scientists, who frequently reject epidemiological findings for inappropriate reasons.     

Toxicity of binary mixtures of cadmium-copper and carbendazim-copper to the nematode Caenorhabditis elegans

For ecological risk assessment, the additive model may be used to empirically predict toxic mixture effects. Detailed toxicity tests were performed to determine whether effects of mixtures of copper-cadmium and copper-carbendazim on Caenorhabditis elegans were similar to the effects of the individual compounds. Effects on the course of reproduction, the length of the juvenile period, the length of the reproductive period, and body length were analyzed. Dose-response data were compared to the additive model and tested for four deviation patterns from additivity: No deviation, synergistic/antagonistic deviation, dose ratio-dependent deviation, dose level-dependent deviation. During the exposure, the cadmium-copper effect on reproduction changed from a synergistic, to a dose ratio-dependent deviation from additivity. More cadmium in the mixture decreased the toxicity and more copper increased the toxicity. The effect of copper-carbendazim on reproduction was synergistic at low dose levels and antagonistic at high dose levels and independent of time. Mixture effects on the juvenile and reproductive period were similar to single component effects. It was concluded that the observed time-dependence of toxic interactions was small and that interactions on the timing of reproduction were not found. The additive model underestimated mixture effects on reproduction and body length.     

Assessing environmental risks for established invasive weeds: Dalmatian (Linaria dalmatica) and yellow (L. vulgaris) toadflax in North America

Environmental risk assessments characterizing potential environmental impacts of exotic weeds are more abundant and comprehensive for potential or new invaders than for widespread and well-established species such as Dalmatian (Linaria dalmatica [L.] Mill.) and yellow (L. vulgaris Mill.) toadflax. Specific effects evaluated in our assessment of environmental risks posed by yellow and Dalmatian toadflax included competitive displacement of other plant species, reservoirs of plant disease, animal and insect use, animal toxicity, human toxicity and allergenicity, erosion, and wildfire. Effect and exposure uncertainties for potential impacts of toadflax on human and ecological receptors were rated. Using publicly available information we were able to characterize ecological and human health impacts associated with toadflax, and to identify specific data gaps contributing to a high uncertainty of risk. Evidence supporting perceived negative environmental impacts of invasive toadflax was scarce.     

Integrating biomonitoring exposure data into the risk assessment process: phthalates [diethyl phthalate and di(2-ethylhexyl) phthalate] as a case study

The probability of nonoccupational exposure to phthalates is high given their use in a vast range of consumables, including personal care products (e.g., perfumes, lotions, cosmetics), paints, industrial plastics, and certain medical devices and pharmaceuticals. Phthalates are of high interest because of their potential for human exposure and because animal toxicity studies suggest that some phthalates affect male reproductive development apparently via inhibition of androgen biosynthesis. In humans, phthalates are rapidly metabolized to their monoesters, which can be further transformed to oxidative products, conjugated, and eliminated. Phthalate metabolites have been used as biomarkers of exposure. Using urinary phthalate metabolite concentrations allows accurate assessments of human exposure because these concentrations represent an integrative measure of exposure to phthalates from multiple sources and routes. However, the health significance of this exposure is unknown. To link biomarker measurements to exposure, internal dose, or health outcome, additional information (e.g., toxicokinetics, inter- and intraindividual differences) is needed. We present a case study using diethyl phthalate and di(2-ethylhexyl) phthalate as examples to illustrate scientific approaches and their limitations, identify data gaps, and outline research needs for using biomonitoring data in the context of human health risk assessment, with an emphasis on exposure and dose. Although the vast and growing literature on phthalates research could not be covered comprehensively in this article, we made every attempt to include the most relevant publications as of the end of 2005.     

Mechanisms underlying Children's susceptibility to environmental toxicants

An important public health challenge has been the need to protect children's health. To accomplish this goal, the scientific community needs scientifically based child-specific risk assessment methods. Critical to their development is the need to understand mechanisms underlying children's sensitivity to environmental toxicants. Risk is defined as the probability of adverse outcome and when applied to environmental risk assessment is usually defined as a function of both toxicity and exposure. To adequately evaluate the potential for enhanced health risks during development, both child-specific factors affecting toxicity and exposure need to be considered. In the first section of this article, example mechanisms of susceptibility relevant for toxicity assessment are identified and discussed. In the second section, examples of exposure factors that help define children's susceptibility are presented. Examples of pesticide research from the newly funded Child Health Center at the University of Washington will be given for illustration. The final section discusses the importance of putting these considerations of children's susceptibility into an overall framework for ascertaining relevancy for human risk assessment.     

Sterilization of workers from pesticide exposure: the causes and consequences of DBCP-induced damage in Costa Rica and beyond.

Public health hazards from the use of agricultural pesticides have received increasing attention in developing as well as industrial nations. This article examines a remarkable case of massive sterilization of approximately 1,500 workers in Costa Rica, due to exposure to a toxic nematicide called DBCP 1,2-dibromo-3-chloropropane), applied in large commercial banana plantations. Although the product was used during the 1970s, sterile victims have continued to be diagnosed through the 1980s. The effects include psychological trauma as well as permanent infertility. The case has international repercussions because several hundred workers have filed law suits against the U.S.-based transnational DBCP manufacturers, and because DBCP use was continued during the 1980s in other developing nations. The author analyzes the causes behind this serious impairment. It is argued that the contributing factors include not only biomedical processes and technical dimensions (i.e., how DBCP was used), but most importantly, political-economic factors that explain how and why DBCP was used despite the severe hazard. The crucial determinants pertain to the dominance of short-term profit motives, and the control over information and technology by the manufacturers (who concealed early toxicological research evidence of the reproductive hazards) and by the managers of the banana producer-companies. This case well illustrates problems and injustices from labor exploitation and resource extraction from transnational agro-industries. The article concludes with a brief summary of policy implications from the case.     

Shortened lifespan of nematode Caenorhabditis elegans after prolonged exposure to heavy metals and detergents

The acute toxicities of heavy metals and detergents have been well examined with respect to several endpoints, such as mortality, for application to toxicity tests for environmental assessments. However, chronic influences of these agents on multicellular organisms still need to be determined. Here we studied long-term effects on the lifespan of a free-living nematode, Caenorhabditis elegans, resulting from prolonged exposure to heavy metals or detergents, as well as short-term inhibitory effects on reproduction and growth. These agents inhibited growth of hatched larvae and reproductive capacity in a concentration-dependent manner. They also effectively shortened the lifespan of the adult nematode over the same concentration range. Since toxic effects on both growth and lifespan were observed over similar concentration ranges, where acute toxicities in various endpoints are detected, the shortening of the lifespan can be used as a new endpoint for the assessment of various ecotoxic agents.     

Assessing, mapping and validating site-specific ecotoxicological risk for pesticide mixtures: a case study for small scale hot spots in aquatic and terrestrial environments

Mixture toxicity is a real world problem and as such requires risk assessment solutions that can be applied within different geographic regions, across different spatial scales and in situations where the quantity of data available for the assessment varies. Moreover, the need for site specific procedures for assessing ecotoxicological risk for non-target species in non-target ecosystems also has to be recognised. The work presented in the paper addresses the real world effects of pesticide mixtures on natural communities. Initially, the location of risk hotspots is theoretically estimated through exposure modelling and the use of available toxicity data to predict potential community effects. The concept of Concentration Addition (CA) is applied to describe responses resulting from exposure of multiple pesticides The developed and refined exposure models are georeferenced (GIS-based) and include environmental and physico-chemical parameters, and site specific information on pesticide usage and land use. As a test of the risk assessment framework, the procedures have been applied on a suitable study areas, notably the River Meolo basin (Northern Italy), a catchment characterised by intensive agriculture, as well as comparative area for some assessments. Within the studied areas, the risks for individual chemicals and complex mixtures have been assessed on aquatic and terrestrial aboveground and belowground communities. Results from ecological surveys have been used to validate these risk assessment model predictions. Value and limitation of the approaches are described and the possibilities for larger scale applications in risk assessment are also discussed.     

Children's health and the environment: public health issues and challenges for risk assessment

Infants and children are not little adults. They are uniquely vulnerable to environmental toxicants. To protect infants and children against toxicants, the National Research Council in 1993 called for development of an approach to risk assessment that considers children's unique patterns of exposure and their special vulnerabilities to pesticides. Many aspects of that call were codified into federal law in the Food Quality Protection Act (FQPA) of 1996. This report highlights the central elements needed for development of a child-protective approach to risk assessment: a) improved quantitative assessment of children's exposures at different life stages, from fetal life through adolescence, including acute and chronic exposures, exposures via multiple routes, and exposures to multiple agents; b) development of new approaches to toxicity testing of chemicals that can detect unanticipated and subtle outcomes and that evaluate experimental subjects over the entire life span from early exposure to natural death to replicate the human experience; c) development of new toxicodynamic and toxicokinetic models that account for the unique physiologic characteristics of infants and children; d) development of new approaches to assessment of outcomes, functional, organ, cellular and molecular, over the entire life span; these measures need to be incorporated into toxicity testing and into long-term prospective epidemiologic studies of children; and e) application of uncertainty and safety factors in risk assessment that specifically consider children's risks. Under FQPA, children are presumed more vulnerable to pesticides than adults unless evidence exists to the contrary. Uncertainty and safety factors that are protective of children must therefore be incorporated into risk assessment when data on developmental toxicity are lacking or when there is evidence of developmental toxicity. The adequate protection of children against toxic agents in the environment will require fundamental and far-reaching revisions of current approaches to toxicity testing and risk assessment.     

Occupational ethylene oxide exposure and reproduction

Summary Animal and epidemiological studies on the reproductive toxic effects of ethylene oxide (ETO) were considered in relation to occupational exposure levels (OELs) of ETO in the occupational environment of sterilisation units. Actual exposure levels in sterilisation units at Belgian and Dutch hospitals are presented and compared to data from recent studies conducted elsewhere. The animal studies did not match the actual exposure situation, involving a pattern of high peak levels and low time-weighted average levels. This may be the reason why epidemiological studies show contrasting results; they suggest reproductive toxicity of ETO at actual exposure levels. However, human data are scarce. There is a need for animal studies with a design that reflects the actual exposure situation. Epidemiological studies on reproductive events are also needed and a multi-country study would seem to be a possible approach, provided that the study design and data collection method are standardised.     

Epidemiological approaches in the investigation of environmental causes of cancer: the case of dioxins and water disinfection by-products

I will refer in this paper to difficulties in research in environmental causes of cancer using as examples research on dioxins and on drinking water disinfection by-products (DBPs) that have created considerable controversy in the scientific and wider community. Dioxins are highly toxic chemicals that are animal carcinogens. For many years, evaluation of the carcinogenicity of dioxins in humans was based on case-control or registry based studies. The development of methods to measure dioxins in blood indicated that these studies suffered from extreme exposure misclassification. The conduct of large cohort studies of workers with widely contrasted exposures together with the use of biomarkers and models for exposure assessment, led to convincing evidence on the carcinogenicity of dioxins in humans. The high toxicity of a few dioxin congeners, the availability of a scheme to characterize the toxicity of a mixture of dioxins and related compounds and the long half-life of these compounds facilitated epidemiological research. Contrary to dioxins, trihalomethanes (THMs) and most of the hundreds of DBPs in drinking water are chemicals of low toxicity. For more than 15 years, the main evidence on the carcinogenicity of DBPs was through ecological or death certificate studies. More recent studies based on individual assessment confirmed increases in bladder cancer risk. However even those studies ignored the toxicological evidence on the importance of routes of exposure to DBPs other than ingestion and, probably, underestimated the risk. Persistence of weak study designs together with delays in advanced exposure assessment models led to delays in confirming early evidence on the carcinogenicity of DBPs. The evaluation of only a few chemicals when exposure is to a complex mixture remains a major problem in exposure assessment for DBPs. The success of epidemiological studies in identifying increased risks lies primarily on the wide contrast of exposure to DBPs in the general population that overcomes the significant exposure misclassification. Exposure assessment has been the Achilles heel for studies on dioxins and DBPs and cancer. The combination of powerful study designs, advanced exposure assessment together with a better understanding of mechanisms of disease and the use of biomarkers of exposure, led to the strengthening of the epidemiological evidence.     

Integrated condition indices as a measure of whole effluent toxicity in zebrafish (Danio rerio)

Toxic exposure of organisms interferes with organismal integrity at the biochemical level and ultimately gives rise to effects at the individual level. These effects may result in reductions in ecologically relevant characteristics such as growth, reproduction, and survival. A chronic toxicity test with zebrafish (Danio rerio) was conducted where fish were exposed to 50, 75, and 100% effluent for 28 d under flow-through conditions. Effects of effluent exposure were determined using endpoints of physiological (respiration during swimming), growth (condition, length, and weight), and reproductive (spawning and hatching) processes within the same population. Results clearly indicate that the condition and growth of zebrafish is depressed by exposure to the effluent. Also, increased oxygen consumption was found after 14, 21, and 28 d of exposure. Reproduction proved to correlate well with the condition of the motherfish in the control, and spawning and hatching were significantly depressed by effluent exposure. These results indicate that the evaluation of endpoints describing different ecologically relevant processes provides a rational assessment of the cause-effect relationships of effluent toxicity. This approach can quantify effects on different biological processes and can determine the interactions that occur between these different processes.     

An exploratory analysis of the effect of pesticide exposure on the risk of spontaneous abortion in an Ontario farm population

The toxicity of pesticides on human reproduction is largely unknown--particularly how mixtures of pesticide products might affect fetal toxicity. The Ontario Farm Family Health Study collected data by questionnaire on the identity and timing of pesticide use on the farm, lifestyle factors, and a complete reproductive history from the farm operator and eligible couples living on the farm. A total of 2,110 women provided information on 3,936 pregnancies, including 395 spontaneous abortions. To explore critical windows of exposure and target sites for toxicity, we examined exposures separately for preconception (3 months before and up to month of conception) and postconception (first trimester) windows and for early (< 12 weeks) and late (12-19 weeks) spontaneous abortions. We observed moderate increases in risk of early abortions for preconception exposures to phenoxy acetic acid herbicides [odds ratio (OR) = 1.5; 95% confidence interval (CI), 1.1-2.1], triazines (OR = 1.4; 95% CI, 1.0-2.0), and any herbicide (OR = 1.4; 95% CI, 1.1-1.9). For late abortions, preconception exposure to glyphosate (OR = 1.7; 95% CI, 1.0-2.9), thiocarbamates (OR = 1.8; 95% CI, 1.1-3.0), and the miscellaneous class of pesticides (OR = 1.5; 95% CI, 1.0-2.4) was associated with elevated risks. Postconception exposures were generally associated with late spontaneous abortions. Older maternal age (> 34 years of age) was the strongest risk factor for spontaneous abortions, and we observed several interactions between pesticides in the older age group using Classification and Regression Tree analysis. This study shows that timing of exposure and restricting analyses to more homogeneous endpoints are important in characterizing the reproductive toxicity of pesticides.