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Occupational, industrial and environmental agents
It is ambitious to describe the risk assessment of occupational, industrial and environmental agents, since they are the sum total of all agents which are potentially capable of producing an effect, whether physical, chemical or biological. They are found everywhere and influence the development of an individual. Both synthetic and naturally occurring substances may have significant pharmacological and toxicological properties, but few have been tested. Among the millions of synthetic chemicals registered with national or regional authorities, fewer than 100,000 are currently in commercial or industrial use, and most of these have not been tested for developmental toxicity. Similarly, very few toxins from microorganisms, fungi, plants, and animals have been systematically characterized for effects on development. The agents highlighted in this chapter may be of importance if there is occupational or environmental exposure to women who are pregnant or to men and women in their reproductive years.
In principle, it is difficult to distinguish between industrial and environmental chemicals. Environmental pollutants are usually industrial chemicals released as pollutants into the environment (air, water, or soil) during production, use, waste disposal, recycling, and combustion processes. Others are released from naturally high sources – for example, arsenic in regions with substantial granite deposits or copper smelting, or dioxins from burning of wood. The concentration of a particular industrial chemical may normally be higher in the workplace than in the general environment. However, when an accident occurs, the environmental pollution may exceed the typical workplace exposure. A number of reviews have been published on the reproductive toxicity of industrial and environmental chemicals (see overviews in , , , , , ), but these cover only a small fraction of the total number of chemicals to which women may be exposed in the workplace.
Individual risk characterization is much more difficult with occupational or environmental exposure to chemical or physical agents than with a particular drug treatment, because:
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a pregnant woman is rarely exposed to a single agent;
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quantifying workplace or environmental/household exposure levels is difficult, expensive, time-consuming, and often would have to be done prospectively to be useful;
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there is a lack of data regarding kinetic properties (absorption, distribution, metabolism, excretion) of most chemicals in the mother and the embryo/fetus.
There is legislation in most developed countries preventing gender discrimination in employment and protecting the rights of women to work during pregnancy. Alongside this, there is the need for adequate information on the possible risks of exposure to chemicals in the workplace. Most jurisdictions require the production of Materials Safety Data Sheets (MSDSs). These should include any information that exists on the reproductive and developmental toxicity of the chemical. However, in practice, MSDSs rarely provide a useful reference source other than identification of the constituents of the product; the same lack of information on potential for reproductive effects holds true for physical and biological agents.
Since it is difficult to specify the upper safe limits of workplace exposure for pregnant women because of the lack of data, general occupational exposure limits (OELs) for the agent in question are often used as a guide. An OEL is the amount of a workplace health hazard that most workers can be exposed to without harming their health. They are advisory, not regulatory limits. Most OEL values are for time-weighted average (TWA) exposures over an 8-hour working day. For some agents, higher short-term exposure limits (STELs) are also recommended. These are 15 minute TWAs that should not be exceeded at any point during the working day. In the USA, 8-hour OELs are recommended by the American Conference of Governmental Hygienists (termed threshold limit values – TLVs) and by the National Institute for Occupational Safety and Health. The Occupational & Safety Health Administration refers to these recommendations in setting enforceable permissible exposure limits (PELs) to protect workers against the health effects of exposure to hazardous substances. PELs are regulatory limits on the amount or concentration of a substance in the air. They may also contain a skin designation (see http://www.osha.gov/dsg/topics/pel/index.html ). In the EU, Directives recommend indicative occupational exposure limit values (IOELVs), which can be implemented nationally into values that are usually, but not always, identical to IOELV recommendations; national values may or may not be legally binding. For an overview of global OELs for over 6000 specific chemicals, see ; for EU IOELVs, see, for example, the British workplace exposure limits ( ). OELs are regularly updated in many countries, but they are not, in the main, based upon reproductive health data or concerns.
In accordance with the maternal protection laws in many countries, pregnant women should not be exposed to toxic, infectious, ionizing or carcinogenic substances. However, in practice many workplaces require women to handle potentially toxic compounds and do not take into account the possibility that workers might already be pregnant. In addition, non-specific symptoms have to be considered when discussing the tolerability of workplace or household contaminants. If pregnant women complain of repeated symptoms in the workplace – such as headaches, emesis, vertigo – this should be taken seriously. Such recurrent disorders can endanger the normal course of pregnancy. Women may also have exaggerated responses to exposure simply because they are pregnant. This is often reported in relation to nausea and vomiting in pregnancy. For evaluating approaches to exposure during pregnancy, see .
With respect to awareness of an increased risk of birth defects from environmental pollution, birth defect monitoring systems would be of help. However, birth defect monitoring and surveillance systems seldom methodically measure environmental exposure. Only in the case of a cluster of defects with suggestions for pollution-related causation might such studies be performed. Absence of a change in the prevalence of birth defects in a population is not sufficient to exclude a (new) environmental developmental toxicant per se , since these monitoring systems are considered too insensitive. Similarly, general population studies (e.g. on rural populations exposure to a variety of pesticides) are seldom sufficiently sensitive to identify any specific chemicals that may be involved. In the case of linkage of occupational exposures to reproductive hazards, the epidemiologist has to demonstrate that reproductive outcome is worse than expected when the mother or father has a specific occupational exposure, and that this is not due to confounders such as disease, maternal age, cigarette smoking, etc. ( ).
2.23.1
Solvent exposure in general
Toxicology
Many solvents are lipid soluble and well absorbed. Common organic solvents include alcohols (see Chapter 2.21 ), glycol ethers , ethylether , hexane , tetrachloroethane , toluene , and xylene . Products such as degreasers, paint thinners, varnish removers, lacquers, silk-screening inks, and paints, also contain solvents. Exposure to one single solvent is rare; more frequently exposure is to mixed solvents by the inhalational and/or dermal routes. Hence, much of the epidemiology has been conducted on mixed or unspecified solvent exposure both at work and at home.
Exposure to solvents has been associated with significant reductions in fertility in women working in agriculture ( ), shoe manufacturing, dry cleaning, the metal industry ( , ), and the pharmaceutical industry ( ).
Spontaneous abortions have also been reported to be significantly increased in solvent-exposed women working in various occupations and industries (see , for review). These include pharmaceutical manufacture ( , ), graphics and shoe manufacturing, ( ), laboratories ( ), and semiconductor manufacture (reviewed by ). In some of these occupations, exposure is to several solvents, and in some specifically to glycol ethers, toluene, xylene, or aliphatic hydrocarbon solvents.
The influence of maternal occupational exposure to solvents on fetal growth has been studied in specific industries and in population-based studies. The evidence from the former is inconsistent but evidence from the latter shows an increase in the risk of small-for-gestational-age babies (see review by ).
Early studies on the Finnish population reported an association between maternal occupational exposure to solvents in the first trimester and CNS defects in the offspring ( , ), but later studies on the same population did not show an association ( ). In a meta-analysis of pregnancy outcome following maternal occupational exposure to organic solvents in the first trimester, it was concluded to be associated with a tendency towards an increased risk of spontaneous abortion (from five studies with 2899 subjects) and with a significantly increased risk of major malformations (from five studies with 7036 subjects) ( ). An increased risk of major malformations and previous miscarriage was found in a Canadian study of women exposed occupationally to solvents in the first trimester through employment as factory workers, laboratory technicians, artists, graphic designers, and printing industry workers; importantly, maternal symptoms during exposure were predictive of an increased risk of malformations ( ). An increased risk of major malformations was also reported in a cohort of Danish laboratory technicians with exposure to organic solvents ( ). French studies on maternal occupational exposure to single organic solvents or to mixtures of solvents during the first trimester have reported a significantly increased risk of cleft lip with/without cleft palate ( ), and of major malformations, including oral clefts, urinary malformations and male genital malformations ( ). In both studies, the risk was related to the level of exposure and in the latter study the risk was associated with detection of metabolites of glycol ether and chlorinated solvents in maternal urine collected during early pregnancy ( ). Previous studies have not found an association between exposure to glycol ethers and malformations (see for review, ). Significant increases in the risk of neural tube defects and congenital heart defects (but not orofacial clefts) in association with maternal occupational exposure to solvents, particularly chlorinated solvents, has been reported in the US National Birth Defects Prevention Study ( , ).
Some solvents are known to be neurotoxic and there have been a few studies on the neurodevelopment of children born to women with occupational exposure to solvents during pregnancy ( ). Outcomes studied included general developmental neurobehavioral assessments, motor function, vision, language, attention, hyperactivity, and intelligence. Five of the six studies showed some deleterious effects (see for review), as has a more recent study ( ).
Non-occupational exposure to organic solvents in the form of paint fumes in the home environment have been studied in the large Danish National Birth Cohort, comprising 19,000 mothers, of which 45% reported exposure to paint fumes during pregnancy when interviewed around the 30th week. No relationship was found between exposure to paint fumes and birth weight or preterm birth ( ); in the 7% reporting exposure in the first trimester, the risk of some types of malformations showed increased odds ratios, but the confidence intervals did not indicate statistical significance.
Exposure of men to solvents may also affect reproductive success. Weak associations between solvent exposure in various occupations and reductions in male fertility have been reported but no specific solvents could be identified ( , ). Spontaneous abortions and congenital malformations in offspring among wives of men exposed to organic solvents have been studied in Finland. A significantly increased risk of spontaneous abortions but not malformations was found in Finland in wives of men exposed to organic solvents for 80 days before conception, but no significant effect was found in association with direct maternal exposure to organic solvents in the first trimester ( ). Male painters in the Netherlands exposed to organic solvents for 3 months before a conception had a significantly increased risk for malformations in their offspring compared to carpenters with little or no solvent exposure ( ). An Egyptian study reported a significant increase in the risk of congenital malformations in the offspring of men occupationally exposed to solvents during the periconceptional period ( ). A meta-analysis to assess the risks of spontaneous abortions and major malformations after paternal exposure to organic solvents concluded that paternal exposure was associated with an increased risk for neural tube defects, but not for spontaneous abortions ( ).
In summary, occupational exposure to solvents, especially if associated with maternal toxicity, has been reported to cause reduced fertility and an increased risk of spontaneous abortion, fetal growth retardation, malformations and neurobehavioral effects in offspring. The effect of exposure of males on pregnancy outcomes in their partners is less clear. Reports on specific solvents are given below.
Recommendation
In general, exposure to solvents should be avoided during pregnancy. At a minimum, exposure should be well below the permissible exposure or general occupational exposure limits (PELs and OELs). Acute exposure is not an indication for termination of pregnancy; neither are additional prenatal diagnostic tests required as long as the mother demonstrates no symptoms. If continuous and significant exposure has occurred, a detailed fetal ultrasound may be offered and fetal growth should be monitored.
Carbon disulfide
Toxicology
Carbon disulfide is neurotoxic. It is used in the manufacture of rayon textiles, cellophane, rubber and agricultural fumigants.
Placental transfer in human pregnancy has been demonstrated ( ). Carbon disulfide-exposed women have been reported to have alterations in their menstrual cycles suggestive of hormonal abnormalities ( ). The results of Finnish studies suggested that female rayon workers exposed to carbon disulfide or wives of male rayon workers have an increased incidence of spontaneous abortion; however, no causal relationship with carbon disulfide exposures could be established ( , ). A higher incidence of congenital anomalies (e.g. heart defects, inguinal hernia, and CNS abnormalities) of 2.4% compared to 1.4% in controls has been briefly reported in a Chinese study of female workers exposed to carbon disulfide ( ). A review of OELs for carbon disulfide, which vary between 1 and 100 ppm concluded that female reproduction may not be adequately protected at exposures around 10 ppm or above ( ). The data are inadequate to assess its reproductive toxicity in humans. There is no clear evidence to indicate that maternal exposure is associated with an increased risk of fetal toxicity.
Recommendation
In view of the possibility of fetal toxicity, exposure to carbon disulfide should be avoided in pregnancy. When there has been significant exposure, this is not an indication for the termination of pregnancy. However, if the mother has had symptoms of toxicity and/or continuous exposure, she may be offered additional prenatal diagnostic measures – e.g. a detailed fetal ultrasound – and should also be removed from exposure, as well as having the workplace monitored for carbon disulfide concentrations.
Chloroform (trichloromethane)
Toxicology
Chloroform is a widely used industrial and laboratory solvent. Interference with implantation and fetal growth retardation has been reported after exposure to chloroform in human pregnancy. Chloroform is also one of the prominent by-products from chlorination of drinking water (see Section 2.23.7 ).
There are a small number of epidemiological studies on pregnancy outcomes following chloroform exposure, but they are difficult to interpret ( , ). Exposure in these studies was usually to chloroform and a varying number of other chemicals. In a study of 492 children of laboratory workers exposed to organic solvents during the first trimester of pregnancy, 148 were exposed to chloroform. The frequency of congenital anomalies was no greater than expected compared with the general population ( ). However, with multi-chemical exposure, establishing a cause-effect relationship is difficult. For spontaneous abortion, no increase in risk was found in 206 women exposed to chloroform in the pharmaceutical industry ( ), but an increased risk was found in women exposed to chloroform in biomedical research laboratories ( ).
Recommendation
Exposure to chloroform should be avoided in pregnancy wherever possible. Certainly, atmospheric levels should be kept to a minimum well below the recommended OELs. Exposure per se is not an indication for termination of pregnancy. In cases where there is chronic exposure and/or severe maternal toxicity, a detailed fetal ultrasound should be offered and fetal growth monitored. The patient should be removed from exposure, and the workplace monitored for chloroform concentrations.
Dichloromethane (methylene chloride)
Toxicology
The main uses of dichloromethane , a halogenated organic solvent, are as a solvent in paint removers, degreasing fluids, aerosol propellants and hair lacquers. It is also used in shoe manufacturing. As a consequence of its widespread use, many workers may be exposed for prolonged periods ( ). Dichloromethane is metabolized readily to carbon monoxide, which may have toxic effects on the developing fetal brain (see Chapter 2.20 ).
There are three published studies on the effects of occupational exposure to dichloromethane in human pregnancy ( , , ). Data from these studies indicate that there was no overall increase in the incidence of congenital malformations or any syndrome of defects. However, there was no significant increase in the incidence of spontaneous abortion.
A single study on environmental exposure to dichloromethane, due to emissions from a manufacturing facility in the USA, found no significant effect on birth weight among 91,302 births when comparing high exposure to low exposure areas ( ).
Recommendation
Exposure to dichloromethane should be avoided in pregnancy wherever possible. When there has been significant exposure this is not an indication for termination of pregnancy. However, if the mother has had symptoms of toxicity and/or continuous exposure, she may be offered additional prenatal diagnostic measures, such as a detailed fetal ultrasound. The patient should be removed from exposure, and the workplace monitored for dichloromethane concentrations.
Tetrachloroethylene (perchloroethylene, PERC)
Toxicology
Tetrachloroethylene is widely used in the dry-cleaning industry, and exposure of women is common, especially in small businesses where industrial hygienic practices may be inadequate. There are experimental and epidemiological data suggesting a carcinogenic potential of PERC ( ). A number of studies have shown an increased risk for spontaneous abortion of about two-fold in women exposed to tetrachloroethylene in the laundry and dry-cleaning industry, and the risk is increased in more heavily exposed women ( , , , , , ).
No increase in the incidence of low birth weight children or congenital malformations was reported in a Canadian study ( ). None of the other studies were adequate to draw any conclusions about these outcomes.
Maternal exposure to volatile organic compounds, such as PERC, was found to influence the immune status of the newborn ( ). In summary, the data indicate an increased risk of spontaneous abortion associated with occupational exposure, but data are inadequate regarding other outcomes of pregnancy.
Recommendation
Exposure to tetrachloroethylene should be avoided during pregnancy wherever possible. Nevertheless, when there has been significant exposure this is not an indication for termination of pregnancy. However, if the mother has had symptoms of toxicity and/or continuous exposure, she may be offered additional prenatal diagnostic measures, such as a detailed fetal ultrasound including control of fetal growth. The patient should be removed from exposure, and the workplace monitored for tetracholorethylene concentrations.
Toluene
Toxicology
Toluene ( toluol , methylbenzene ) is a widely used solvent in the paint, metal-cleaning products and adhesive applications (shoes) industries. Besides the industrial applications, toluene has been used as a recreational drug as an alternative to ethanol (see Chapter 2.21 ). Toluene is a difficult product to regulate in the workplace and elsewhere because an individual can detect the sweet odor at approximately 3 ppm and the TLV is 25 ppm. Thus, only solvent monitoring of the workplace can establish exposure levels.
Symptoms in the pregnant woman can be the first evidence of substantive exposure – dizziness, headaches and hallucinations can be one sign associated with the workplace or with use of the product. It is often difficult to separate the symptoms of pregnancy nausea and vomiting from toxic effects of the solvent. In either case, it will be necessary, if the symptoms persist, to remove the woman from the specific work area. As with ethanol, dose is a principal concern.
The majority of information on toluene exposure in pregnancy comes from recreational use (solvent abuse). High exposures are associated with intrauterine growth retardation and with congenital anomalies ( ). In more than 30 cases of exposure to toluene via chronic recreational use to the point of “getting high,” both maternal effects (e.g. acute intoxication, chronic ataxia, and atrophy of the cerebellum upon MRI examination) and fetal effects similar to the fetal alcohol syndrome have been regularly noted ( ). In 56 patients with reported solvent abuse, 12 patients (21.4%) delivered preterm infants, nine infants (16.1%) had major anomalies, seven (12.5%) had fetal solvent syndrome facial features, and six (10.7%) had hearing loss ( ).
Occupational exposure has been associated with reduced fertility ( ) and spontaneous abortion ( ). A Canadian occupational exposure study on maternal solvent exposure and the occurrence of birth defects noted that most of the excess in defects was associated with toluene exposure ( ).
A review on the reproductive effect of toluene highlights that maternal solvent abuse, with intermittent high-level exposures, is more detrimental to fetal development than occupational exposures in which there is relatively constant low-level exposures ( ).
Recommendation
The difficulty with occupational and environmental exposure to toluene compared with its abuse is similar to the use of alcohol (ethanol). Chronic abusive high levels resulting in persistent and acute symptoms, for both ethanol and toluene, result in impaired children. Chronic exposure in the workplace to levels resulting in substantive maternal symptoms is thought to place the offspring and mother at risk. Thus, it is recommended that if the pregnant woman is having symptoms (whether exaggerated responses to noxious odors during pregnancy or intoxication because of the excessive levels of solvent), she should not return to the workplace in her usual capacity until environmental monitoring data demonstrate that levels of toluene and any other solvents are well below the regulated levels (PEL, OEL), remembering that odor detection is very low at 3 ppm, while regulatory levels are 25 ppm. Even if the levels of toluene are below the acceptable 8-hour threshold, the patient still may have to be moved to a non-solvent area because of enhanced sensitivity to odors and persistent and regular vomiting and nausea. It is recommended that the status of both mother and conceptus be more closely monitored throughout the pregnancy. Nevertheless, when there has been significant exposure this is not an indication for termination of pregnancy. However, if the mother has had symptoms of toxicity and/or continuous exposure, she may be offered additional prenatal diagnostic measures, such as a detailed fetal ultrasound including control of fetal growth.
2.23.2
Formaldehyde and formalin
Toxicology
Formaldehyde is a hydrocarbon that is widely used as a disinfectant and tissue preservative. Formalin is a solution of formaldehyde in water, often with 10–15% methanol to prevent polymerization.
One study reported that occupational exposure to formaldehyde was significantly associated with delayed conception ( ). Information on spontaneous abortion is inconsistent. In female hospital workers, some have reported no effect ( , ), while others have found a significant effect ( ). However, in addition to formaldehyde, such workers are also likely to have been exposed to other hazardous agents, such as anesthetics and ionizing radiation. Weak associations between spontaneous abortions and formaldehyde exposure have been reported in cosmetologists ( ), laboratory workers ( ), and wood workers ( ).
No significant association was observed between maternal occupational exposure to formaldehyde during the first 3 months of pregnancy and congenital anomalies ( , ).
A systematic review of epidemiological studies on occupational exposure to formaldehyde and reproduction found 16 studies relating to exposure of women. While recall bias and confounding could not be ruled out, the meta-analysis showed a significantly increased risk of spontaneous abortion from nine studies, and of all adverse pregnancy outcomes combined (spontaneous abortion, low birth weight, congenital malformation) from 12 studies ( ).
Non-occupational exposure to formaldehyde through ambient air has also been studied. Higher ambient air exposures to formaldehyde tended to increase the risk of low birth weight and of unspecified congenital heart defects ( , ).
Recommendation
Exposure to chronic or high concentrations of formaldehyde and formalin should be avoided in pregnancy wherever possible. Atmospheric levels should be kept to a minimum, well below the recommended OELs. Exposure per se is not an indication for termination of pregnancy; as a rule, additional prenatal diagnostic tests are not required.
2.23.3
Photographic/printing chemicals
Toxicology
Many substances used in photography and printing are highly irritant and corrosive (see overview in , , ). The most commonly used chemicals are: acetic acid , ammonium sulfate , ammonium thiocyanate , ammonium thiosulfate , bromine/potassium bromide , citric acid , diethylenetriaminepenta acetic acid ( DTPA ), ethylenediamine tetra acetic acid ( EDTA ; ferric ammonium salt of EDTA ), glycol ethers , hydrocarbon solvents , hydroxylamine , 3-phenylenediamine , 4-phenylenediamine , potassium carbonate , sodium benzoate , sodium sulfite , and sulfur dioxide .
There are no data available on the potential toxic effects in human pregnancy for the majority of chemicals used in the photographic/printing industry.
Exposure to ammonia gas is also common, due to accidental spills in photographic processing. Because ammonia is an irritant, it is difficult for workers to remain in the workplace. Therefore, most exposure to ammonia is acute. Ammonia is rapidly metabolized in humans with normal liver function. There is no information on occupational ammonia exposure and human pregnancy outcomes. High doses of bromine salts are toxic. There is one case report concerning an infant who was found to have high serum bromide levels at birth. The mother had handled photographic chemicals during her pregnancy. At birth the child was hypotonic, but once the bromism had resolved the early childhood development was normal ( ). Work in printing and related trades has been associated with reduced fertility in men ( ), and with no effect in men, but reduced fertility in women in association with exposure to toluene ( ; see also Section 2.23.1 ).
Recommendation
Based on the very limited data available, exposure to high concentrations of photographic and printing chemicals should be avoided in pregnancy, wherever possible. If spills do occur, it is recommended that pregnant women avoid the area and allow others with appropriate protective gear to clean up the spillage. It is important that the atmospheric levels are well below the recommended OELs. Exposure per se is not an indication for termination of pregnancy.
2.23.4
Pesticides
Pesticides in general
There is a lot of literature on male and female occupational and non-occupational exposure to pesticides in relation to fertility and pregnancy outcomes (for reviews, see , , , , ). These reviews concluded that while there is some evidence that exposure to pesticides contributes to male and female infertility, the evidence on spontaneous abortion, preterm birth, birth weight, stillbirth, and congenital malformations are inconsistent, and firm conclusions cannot be drawn, either for occupational exposure (gardening, farming, agriculture, horticulture, greenhouse work, etc.) or for those living in areas where pesticides are applied. A review of eight studies on maternal occupational exposure to pesticides and neurodevelopment in offspring concluded that there was a negative impact; exposures were usually to mixtures of pesticides from the organophosphate, carbamate, or organochlorine groups and specific pesticides were not identified ( ). Studies that ascertain all pesticide exposures may be insensitive with regard to identifying individual pesticides that may carry a risk. They also do not assess exposures to other agents (e.g. solvents), and do not differentiate between workers that do or do not use personal protective equipment.
A number of studies have focused on the genital tract abnormalities, cryptorchidism and hypospadias, in male offspring of pesticide workers because of the role of an endocrine mechanism in the etiology of these conditions, and the endocrine modulating properties of some pesticides, such as organochlorines. A meta-analysis of 16 epidemiological studies on maternal and/or paternal occupational exposure to pesticides and cryptorchidism in sons indicated that while there were weak associations (often not statistically significant) with relevant occupations or maternal serum, milk or fat levels of certain pesticides, there were other studies showing no association ( ). Two ecological studies in geographical areas with varying levels of pesticide use also showed associations with higher levels of pesticide use and cryptorchidism ( ). A meta-analysis of nine studies on hypospadias showed marginally significant, increased risks from maternal or paternal exposure to pesticides ( ). More recent studies not included in the above-mentioned meta-analyses have reported significantly increased risk of male genital malformations in sons of women occupationally exposed to pesticides ( ), and of cryptorchidism ( ), and no increased risk for hypospadias ( ).
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