Phenoxyacetic acid derivatives and chlorinated dibenzodioxins

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Toxicology

Agent Orange, the active constituents of which are 2,4-dichlorophe-noxyacetic acid (2,4 D) and 2,4,5-trichlorophenoxyacetic acid (2,4, 5-T), was widely used as a defoliant in the USA, and in Southeast Asia during the Vietnam War. There is particular concern about one of its trace contaminants, 2,3,7,8-tetrachlorodibenzo-p-diOxin (TC'DD, often referred to as dioxin, see below).

There is conflicting evidence of an association between Agent Orange and birth defects (see overview in Schardcin 2000). There are three reports that suggest that there is an association with congenita! malformations. The US Environmental Protection Agency (EPA) reported an increase in the incidence of spontaneous abortion in an area sprayed with herbicides including Agent Orange, compared with that found in two control areas (EPA Federal Register 1979). However, there are serious methodological limitations in this study which make interpretation of the data very difficult (Tognoni 1982). The other two studies describe the incidence of neural tube defects (Field 1979) and congenital anomalies (Hanify 1981) in agricultural areas using 2.4,5-T herbicides.

There are several reports of investigations where no association between 2,4,5-T exposure and an increased incidence of either spontaneous abortions or any specific type of congenital anomalies was observed (Smith 1982, Townsend 1982, Thomas 1980, Nelson 1979).

Concerns have been raised regarding the possibility that paternal exposure to Agent Orange/TCDD may have increased the incidence of congenital anomalies among the offspring of Vietnam veterans. Although there have been several reports of children with malformations allegedly due to paternal exposure to Agent Orange during the Vietnam War, the results of three comprehensive case-control studies indicate that no causal relationship could be established. No pattern of congenital anomalies was observed (Wolfe 1995, Donovan 1984, Erickson 1984). Compared with the plentiful studies on paternal exposure of US Vietnam veterans, there is little published material about the health of the exposed (pregnant) population of Vietnam. Moreover, a biologic plausibility regarding paternal teratogenicity, for example by indicating a mutagenic effect of Agent Orange/TCDD on spermatogonia and further developing sperm, has not been demonstrated.

Chlorinated dibenzodioxins are contaminants formed during the manufacture and combustion of organochlorine compounds. In July 1976, at Seveso in Italy, there was an accident at a pesticide manufacturing plant resulting in the release of TCDD into the environment. Numerous investigations followed this incident, involving the exposure of approximately 37 000 people, some of whom developed chloracne. The majority of studies found no association between exposure to TCDD/Agent Orange and an increased incidence of congenital anomalies (see overview in Schardcin 2000, Smith 1982, Townsend 1982, Thomas 1980, Nelson 1979). Only one investigation indicated that the TCDD release was associated with an increase in adverse pregnancy outcome (Commoner 1977). Detailed analysis of this report indicates serious flaws in data collection, with no assessment of the relationship between exposure and stage of fetal development (Friedman 1984). Furthermore, none of the reports provide clear proof of exposure to TCDD/Agent Orange in the populations studied.

Recommendation. Exposure to TCDD/Agent Orange must be strictly avoided in pregnancy. However, if exposure has accidentally occurred this is not an indication for termination of pregnancy. It has to be decided upon individually as to whether additional diagnostic measures should be undertaken.

2.23.8 Metais

Arsenic (see also Chapter 2.22)

Toxicology

Arsenic (As) is an element. Some commonly encountered inorganic arsenic salts include the trivalent sodium arsenite and the pentavalent sodium arsenate. Arsenic is a by-product of smelting, and a contaminant in hazardous waste sites. Furthermore, arsenic can naturally leach from certain types of rock - e.g. granite - resulting in substantially elevated levels of arsenic in the aquifers used for drinking water. This is a particular problem for unfiltered well water. Organic arseni-cals have been used in the past for the treatment of syphilis. Arsine (AsH3) is an arsenical that is used as a gas in manufacturing semiconductors. Monomethylarsonic acid is used in some herbicides.

Both the inorganic arsenic salts and the organic arsenicals cross the human placenta and have been shown to accumulate in the placenta and the fetus. Trivalent arsenite demonstrates enhanced cytotoxicity compared with the pentavalent arsenate.

Occupational and environmental exposure to arsenic has been associated with adverse events in the conceptus. Nordstrom (1978) studied spontaneous abortions, birLh weight of offspring, and congenital defects in Swedish workers in and around a smelter. Significant increases in malformation rates in the fetuses and newborns of the female workers, as compared to other women living in the region, were found. There were 13 malformations among 253 women who worked in the plant, compared to 694 among 24 018 in the region (p < 0.05). Birth weights were reduccd, and spontaneous abortions increased.

Environmental exposure, as noted by elevated levels in soil and water, to arsenic resulted in the birth of low birth-weight babies. In 2003, associations between elevated water levels of arsenic (40|ig/l) in communities and an increased incidence of fetal growth restriction (FGR) were reported in Taiwan (Yang 2003) and in South America (Hopenhayn 2003).

Recommendation. Evidence is developing that arsenic can increase the incidence of pregnancy loss and fetal growth restriction. If arsenic is a known or potential contaminant of soil or water (especially private wells), both the water/soil and blood/urine levels should be monitored. Eliminating exposure is the recommended intervention (e.g. using filtered water or bottled water in cases of water contamination), and following the pregnancy closely to monitor fetal growth and development.

Toxicology

Cadmium is widely distributed in industrialized countries. Besides occupational exposure, some of the most common incidents are exposure to tobacco smoke and to old and poorly coated cookware, and from ingesting shellfish and kidney. For example, using an old silver-plated pitcher for an acidic drink like lemonade can lead to acute gastritis (Miller 2004), while 2-4|ig of cadmium can accumulate in a one-pack-a-day smoker. Cadmium levels are significantly increased in placentas from women who smoke during pregnancy (Eisenmann 1996). In the past, most toxicologists have considered cadmium to be initially a renal toxicant; however, evidence in both animal and human in vitro and in utero studies have demonstrated that the placenta is more sensitive to the toxic effects of cadmium than is ihe kidney (Miller 2004, Wier 1990), Occupational exposure is usually found in welders, and workers in foundries and cadmium battery factories. Two case reports identified cadmium intoxication in women who taught welding. They lost multiple pregnancies, and could not carry a child beyond the second trimester (Eisenmann 1996).

Animal studies demonstrate that cadmium is concentrated in the placenta and appears to damage it, resulting in the demise of the fetuses (White 1990, Levin 1980, Parizek 1964). Such was the observation for the two human case reports. Malformations (hydrocephalus) were only noted when the rat fetuses were directly injccted, bypassing the rodent placenta (White 1990).

Recommendation. Exposure to cadmium has certainly been noted in humans, During pregnancy, the apparent concern is the bioaccumulation in the placenta, leading to compromise and possible necrosis that is dose-dependent. Current limited human studies would suggest that if a pregnant woman is demonstrating signs of renal toxicity - increased beta-microglobu-lins and cadmium in their urine - then very close monitoring of the pregnancy, with determination of the source of cadmium to eliminate any further exposure, is required to reduce risk of pregnancy loss. Cadmium has a halflife of 30 years.

Toxicology

Lead toxicity has been recognized for over 1000 years. Poisoning by organic lead (tetraethyl lead) is associated primarily with CNS

toxicity which is distinguishable from that produced by inorganic lead. The overall toxicity of the organic form would seem to be due to the molccular species as a whole, rather than the metallic constituent alone.

Organic lead is much more rapidly absorbed than inorganic salts, by all routes, and is highly lipid-soluble, rapidly passing the blood-placenta barrier from 12 weeks onwards, and the fetal blood-brain barrier (Rabinowitz 1988). The effects on human reproduction are not unique. There have many unsubstantiated reports that women who worked in occupations with high lead exposure (white lead industries, potteries) had high miscarriage and stillbirth rates and gave birth to stunted, abnormal babies, but there are no epidemiological studies or case reports specifically on organic lead. It was a commonly held belief that lead was an abortifacient; however, as lead is a cumulative poison and is ubiquitously distributed in the environment, it is potentially a reproductive hazard for men and women (Schardein 2000, Miller 1993, Manton 1992, Bornschein 1984, Barlow 1982, Scanlon 1975). There is no conclusive evidence to suggest that maternal exposure to lead is associated with an increased risk of major structural malformations. There have, however, been some unconfirmed indications that there may be an increased risk of minor anomalies in women with high blood lead levels, which in some instances seemed to be a dose-related effect (Schardein 2000, Miller 1993, Rabinowitz 1988, Bornschein 1984, Needleman 1984, Barlow 1982, Scanlon 1975).

Other forms of fetal lead toxicity have been reported. Some studies have shown a significant association between chronic exposure to high concentrations of lead and premature delivery, decreased gestational maturity, low birth weight (Kaul 2002), and reduced postnatal growth. Exposure to high concentrations of lead in the third trimester has been associated with an increased risk of macrocephaly.

There are a number of case reports indicating neurological deficits and poor IQ scores in the offspring of lead-exposed mothers, even with a moderate increase of maternal lead level (<300|ig/l) (see overview in Schardein 2000, Miller 1993, Bellinger 1992, 1991, Davis 1990, Barlow 1982). However, other workers have reported no adverse effects on language development in children studied from birth to 3 years old (Dietrich 1993, Ernhart 1989). Two other studies have found no association between prenatal lead exposure and intelligence at 4 years of age (Dietrich 1993, Davis 1990). Iron deficiency anemia often occurs in populations with high lead exposure, and has also been associated with lower scores on mental and psychomotor indices.

The results of two large prospective studies in the smelter town Port Pirie (Australia) and in Boston showed no significant association between prenatal lead exposure and child intelligence during the preschool period (Bellinger 1991, McMichael 1988).

A third prospective study of lead exposure and early postnatal development was performed in two groups of pregnant women, one group from a smelter town and the other group from a non-lead-exposed town in Yugoslavia (Wasserman 1994). The children were followed to 4 years of age. The authors concluded that continuing lead exposure is associated with cumulative losses in cognitive function, particularly those involving perceptual-motor integration, during the preschool years. Collectively, the findings of these three prospective studies indicate that the most sensitive period for exposure to lead occurs from the age of 18 months onwards.

One of the difficulties in trying to assess the risk of fetal toxicity for an individual pregnant woman is that the amount of lead to which she (and the fetus) are exposed is not always known. Thus, the majority of the published data refer to low, medium, and high exposure.

In general, maternal blood lead concentrations within the normal range (i.e. <10[ig/dl) have not been associated generally with an increased risk of fetal toxicity. However, questions continue to be raised for values >5 ng/dl. In adults, the blood lead concentrations regarded as toxic and requiring chelation therapy are in the range of>60pg/dl. In pregnant women, blood lead concentrations >30 [tg/dl would be cause for concern. At concentrations which cause severe maternal toxicity (>100|.ig/dl), an increased risk of fetal loss may occur. In such circumstances, the uterine muscles relax and the fetus is expelled from the uterus. It is not known whether this is due entirely to the high concentrations of lead per se, or whether it is secondary to the maternal toxicity (see overview in Schardein 2000, Rabinowitz 1988, Barlow 1982, Scanlon 1975). In children with brain dysfunction following in utero exposure to lead, the blood concentrations of lead are usually >35 pg/dl. Lead concentrations of>40|tg/dl in children are regarded as toxic, and require chelation therapy.

Women who live in older homes may be exposed to higher levels of lead due to deteriorating lead-based paint. If paint needs to be removed (preferably by experts) from a home, pregnant women and children should remain out of the way. Lead crystal glassware and some ceramic dishes may contain lead, and pregnant women and children should avoid frequent use of these items. Other unexpected sources of lead in the home may include such items as the wicks of scented candles and the plastic (polyvinylchloride) grips on some hand tools. Jobs that are related to lead, and thus contamination with lead, include painters, smelters, and workers in auto repair shops, battery manufacturing plants, and certain types of construction (Sallmen 1992).

Of particular concern regarding lead exposure are specialty food products produced in the homes - for example, ethnic foods cooked in lead pots brought into the US by family members. These foods have a sweet taste provided by the lead (NYCDH 2004). Further, women are obtaining elevated levels of lead from aryvedic medicines produced in non-health inspected sites. Careful monitoring of all cookware and knowing the origins of prepared foods and medicines can assist in reducing lead exposure. In New York (USA), there arc mandatory requirements for all pregnant women to be screened for lead at their first prenatal visit (Miller 2004).

At a minimum, pregnant women should be screened for lead (by questionnaire or blood lead level), A factor that influences judgment regarding lead exposure is whether the lead exposure is acute or chronic. Measuring bone lead with K-X ray fluorescence (K-XRF) can provide a history of chronic exposure (Miller 2006). Tibia and patellar bone lead provides the index for chronic versus acute exposure to lead. This assessment can be helpful in predicting whether large amounts of lead will be mobilized from the bone as the pregnancy continues.

Recommendation. All (occupational, environmental, home, medicines, foods) exposure to lead should be avoided. If there is any known exposure to lead, women who are planning a pregnancy or currently pregnant should have, at a minimum, their blood lead level checked. Also, low exposure levels have been shown to influence mental development. A water supply running through lead pipes with the usual water pH value is not a major concern; however, standing water in lead-sealed containers can lead to significant exposure. Accidental exposure is not an indication for termination of pregnancy. If significant (continuous) exposure has occurred before or during pregnancy, maternal blood lead concentrations should be determined, along with the possibility of the use of KXF screening, which is now just considered for pregnant women.

Mercury

Toxicology

Mercury enters the environment from natural and man-made sources (such as coal-burning, and other industrial pollution). There are two main types of mercury; inorganic (metallic mercury, used in thermometers and sphygmomanometers), and converted by bacteria (organic mercury, e.g. methyl mercury, as accumulated in the fatty tissues of fish or used in seed dressings as an antifungal agent). While trace amounts of mercury are present in many types of fish, mercury is most concentrated in large fish that eat other fish, such as swordfish and shark; these fish contain more than 1 mg/kg of mercury (EFSA 2004). There is an extensive literature on the reproductive toxicology of mercury both in man and animals (Clarkson 2006). One of the main problems with the published data is that often there is no distinction made between inorganic and organic mercury, and the results are based on total mercury measured (Barlow 1982). However, more recently, species differentiation has been reported (Clarkson 2006).

The cffccts of accidental exposure to high-dose methyl mercury on pre- and postnatal development have been well documented as Minamata disease, including CNS damage. Ingestion of contaminated fish in lapan, ingestion of Hour made from treated grain in Iraq, and ingestion of pork contaminated with phenyl mercuric acetate have all resulted in poisoning. An interesting publication concerned two heavily contaminated Minamata areas - Modo (M) and Akasaki (A) - comparing stillbirth and spontaneous abortion before and between 1956 and 1968, when the mercury contamination became serious (Itai 2004). Before contamination, the "abnormal pregnancy" rate was 7.0% in M and 5.4% in A; this rose to 18.1% (M) and 14.2% (A) after contamination.

The evidence linking metallic mercury and its inorganic ions to birth defects in humans is less clear (Cox 1999). Furthermore, it is often difficult to interpret the results of studies where exposure to mercury salts has occurred, because the uptake and distribution of the salts may differ from that of metallic mercury.

While there arc many studies showing that mercury is available to the fetus, there are conflicting data regarding whether or not the placenta concentrates mercury (Yoshida 2002, Barlow 1982). Acute inhalation of mercury vapor by pregnant women has resulted in comparable levels of mercury in maternal and neonatal blood samples (Lien 1983). The blood level of mercury in populations differs according to the food intake: in Germany it is<l(ig/í; the level is higher in Sweden and Japan; and in the Inuit the level may be 16|ig/l (maternal blood level) and 35 jig/I (cord blood), according to Bjcrrcgard (2000).

There is also conflicting evidence whether or not metallic mercury causes birth defects, such as CNS anomalies, cleft palate, and skeletal defects (Stewart 2003, Ratcliffc 1996, Ericson 1989, Brodsky 1985, de Rosis 1985). The same conflict exists regarding cognitive shortcomings after maternal normal-to-moderate fish intake (Trasande 2006, Oken 2005, Myers 2003, Grandjean 1997). In a 2006 report, the Seychelles research team (Davidson 2006) determined that with low doses of meHg in fish, there was a bell-shaped curve in performance as the meHg level increased in the children. Such a result supports the importance of other constituents of fresh fish which contribute to the overall well-being of the child - e.g. 3-omcga fatty acids.

Regarding thiomersal (see also Chapter 2.7), a convincing publication by Heron (2004) found no evidence that early exposure to mercury in thiomersal had any deleterious effect on neurologic or psychological outcome.

No association with possible occupational exposure to mercury during early pregnancy was seen in a case-control study of 4915 children with congenital anomalies (Matte 1993). No increase in the incidence of cither spontaneous abortion or birth defects was found in the postal survey of 3212 pregnancies in dental workers who prepared more than 40 mercury amalgams per week (Brodsky 1985). No significant increase in the frequency of congenital anomalies was observed among 120 pregnancies in women who were occupationally exposed to mercury vapor in a lamp factory (de Rosis 1985).

Furthermore, there were no consistent patterns of adverse effects among 8157 infants born to women who worked during pregnancy as dentists, dental assistants, or dental technicians (Ericson 1989).

The results of another study in dentists and dental assistants has indicated that women with high occupational exposure (i.e. who prepare >30 amalgams per week and have poor occupational hygiene practices) were less fertile and took longer to conceive (Rowland 1994). This again is in contrast with the negative outcome of an epidemiological study regarding dental filling placement during pregnancy and low birth weight (Hujoel 2005). There is evidence that there is an increased risk of spontaneous abortion amongst the wives of males occupationally exposed to metallic mercury (Cordier 1992). There is no evidence of a teratogenic risk related to maternal dental amalgams. Absorption of mercury from dental amalgams has been found to be low (see Eley 1997, Larsson 1992).

The clinical data and experimental results of studies concerning the potential teratogenic risks associated with the inhalation of mercury vapor from dental amalgam do not warrant restriction of amalgams in pregnant women. The results also indicate that dental personnel are at no greater risk, provided that they have good occupational hygiene (Larsson 1990).

Recommendation. All (occupational) exposure to mercury should be avoided. Low exposure levels have been shown to influence mental development. Acute, inadvertent exposure to inorganic/metallic mercury is not necessarily grounds for termination of pregnancy, and, as a rule; no additional prenatal diagnostic tests are required.

Dental mercury

If indicated, dental amalgam fillings may be restored during pregnancy. However, if it is available and applicable, substitute material may be preferred. Dental amalgam fillings are by no means grounds for "detoxification" with chelating agents!

Consumption of seafood known for having higher levels of mercury contamination (shark, swordfish, tile fish, whaleblubber, and, to a lesser degree, tuna) should be avoided. If chronic significant mercury exposure has occurred before or during pregnancy, maternal blood levels should be monitored.

In 2004, the US FDA (Food and Drug Administration) and EPA (Environmental Protection Agency) made three recommendations for women who might become pregnant, women who are pregnant, and nursing mothers (see also Chapter 4.18) so they can gain the benefit from eating fish while reducing exposure to the harmful effects of mercury:

1. Do not consume fish that contain high levels of mercury, e.g. shark, swordfish, king mackerel or tilefish,

2. Consume up to 12 ounces (2 average meals) a week of a variety of fish and shellfish that are lower in mercury, e.g. shrimp, canned light tuna, salmon, pollock and catfish. Albacore ("white") tuna has more mercury than canned light tuna. Consume no more than 6 ounces (one average meal) of albacore tuna per week.

Otherwise, women are advised not to eat more than one average meal per week of locally caught fish.

2.23.9 Hazardous waste landfill sites

Toxicology

Waste disposal sites are a potential hazard to health. There has been a series of publications to assess reproductive disorders and birth defects in communities near hazardous chemical sites (Boyle 1997, Goldman 1997, Holmes 1997, Kimmel 1997, Savitz 1997, Scialli 1997, Wyrobek 1997). These studies investigated structural anomalies, genetic changes, mutagenesis, stillbirth and infant death, functional deficits, and growth retardation. Menstrual dysfunction, infertility, prcgnancy loss, prcgnancy complications, and effects on lactation were also investigated (Scialli 1997). Problems involved in epidemiological studies of congenital anomalies incorporating measurements of both environmental and genetic factors have also been reviewed by Shaw (1997) and Kipen (1996). Such studies are difficult to perform and interpret because of the numerous confounding factors.

The results of a multicenter case-control study (EUKOHAZCON) of the risks of congenital anomalies associated with residents near hazardous landfill sites in Europe was reported by Dolk (1998B). The results of this study indicated that residents living within 3 km of a landfill site were at a significantly increased risk of having a child with congenital anomalies.

The study group consisted of 1089 live births, stillbirths, and terminations of pregnancy with non-chromosomal congenital anomalies, and 2366 control births without malformations whose mothers resided within 7 km of a landfill site. Twenty-one sites were included in the study. A zone within a 3-km radius of each site was defined as the "proximate" zone of most likely exposure to teratogens. Of the study group, 295 cases and 511 controls lived within 0-3 km of the site, and 794 cases and 1855 controls lived within 3-7 km of the sites, giving a combined odds ratio of 1.33, adjusted for maternal age and socioeconomic status. The risk decreased considerably with distance away from the sites.

The malformations found were neural tube defects, cardiac septal defects, and anomalies of the great arteries and veins. There was borderline significance for tracheoesophageal anomalies, hypospadias, and gastroschisis. There was little evidence of a difference in risks between any of the landfill sites, but the authors point out that the powers to detect such differences were low.

A study surrounded with comments and erratum was published in 2001, dealing with the results of adverse birth outcomes in populations living near landfills (Elliott 2001). Over 8.2 million live births, nearly 125 000 congenital anomalies (including terminations of pregnancy) and more than 40 000 stillbirths were involved. The conclusion was a small excess of congenita! anomalies and low and very low birth weight in populations living near landfill sites without causal mechanisms available to explain the findings. Alternative explanations conferred data artefacts and residual confounding, to name but a few. Hence, for primary prevention interventions there are no indications. The dispute was enriched by Vrijheid (2002), who suggested an increase in risk of chromosomal anomalies similar to that found for non-chromosomal anomalies from 245 cases of chromosomal anomalies who lived within 0-3 km of 23 hazardous landfill sites in Europe. It should be noted, regarding this issue, that their findings suggested that previously reported results for congenital anomalies should not be extrapolated to a wider range of pregnancy outcomes, but should be evaluated separately for each (Staff 1998),

Recommendation. The studies have not conclusively indicated causative factors. Therefore, no advice can be given other than the obvious: no dwellings should be built on or near a (hazardous) landfill site.

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