Children and the unborn child
Consumption of alcohol during pregnancy is associated with a great potential for
developmental defects in the unborn child.
A distinct dysmorphic condition, the foetal alcohol syndrome (FAS), has been associated
with alcoholism in the pregnant mother. The abnormalities most typically associated with
FAS include central nervous system dysfunction characterised by mental deficiency and
microcephaly, growth deficiencies (both length and weight), a characteristic cluster of
facial abnormalities (short palpebral fissures, hypoplastic upper lip with thinned
vermilion, diminished or absent philtrum, deficient eye growth, short nose), and variable
major and minor malformations (cardio-vascular and skeletal defects).
Many studies in laboratory animals clearly demonstrate that alcohol is a potent
developmental toxicant inducing growth deficiency, mortality, and malformations similar to
those seen in humans. Acetaldehyde, the primary metabolite of ethanol, is teratogenic in
mice and induces growth retardation and malformations in rat foetuses similar to those of
ethanol when injected into the maternal animal during organogenesis. (Schardein 2000a).
Suspicions that exposure to tobacco smoke could be hazardous to reproductive function and foetal development date back to early in the present century. It is now generally considered that smoking during pregnancy increases the risk of perinatal mortality, lowers mean birth weight, increases the risk of spontaneous abortion, and has a significant influence of risks of premature delivery, placenta previa, and abruptio placentae. However, it appears that congenital malformations are not associated with smoking. (Schardein 2000b).
Exposure to environmental tobacco smoke (passive smoking) has been reported to be associated with a variety of respiratory disorders in children, including asthma, wheezing, dyspnoea, cough, bronchitis, pneumonia, otitis media, and laryngospasm with anaesthesia induction. Children exposed to passive smoke in the home have more days of school absence, bed confinement, and restricted activity than children in a smoke-free environment. (McCance & Huether 1998).
Tobacco smoke contains more than 3800 different compounds. About 10% of these
constitute the particulate phase, which contains nicotine and tar. The remaining 90%
contains volatile substances such as carbon monoxide, carbon dioxide, cyanides, various
hydrocarbons, aldehydes, and organic acids. Although all of these substances affect the
smoker to some degree, nicotine is generally considered to be the primary substance
responsible for the pharmacological responses to smoking.
Smoking reduces birth weight of offspring and the consensus of over 200 published
studies is that smokers babies weigh, on the average, 170 to 200 g less at birth
than non-smokers babies, with about twice as many babies weighing less than 2500 g
at birth. Reduced birth weight is primarily due to intrauterine growth retardation, rather
than prematurity. The cause of the growth retardation in utero remains highly
controversial, but the available published information supports the direct effects of
nicotine and carbon monoxide as factors causing intrauterine hypoxia as the most likely
mechanism for the effect of smoking on birth weight. There seems to be a dose-response
relation as it has been calculated that the decrease in birth weight is about 8 to 9 g for
each cigarette smoked daily. Smoking fewer than seven to ten cigarettes per day or early
cessation of smoking in pregnancy results in foetal body weights that do not differ
significantly from those of nonsmokers.
Some of the developmentally toxic effects observed in humans have been observed in laboratory animals as well. Foetal growth retardation is also a characteristic in rats and rabbits, in the absence of malformations, at human exposure levels. Increased stillbirths have also been observed in rabbits exposed to the equivalent of 20 cigarettes per day during pregnancy. (Schardein 2000b).5.3 Ambient air pollution
In the past decades the incidence of respiratory allergic diseases in children has increased significantly in the Western world. Current data do not indicate that ambient air pollution attribute significantly to this rise, however, air pollution may cause significant increases in respiratory symptoms and their intensity in persons suffering from asthma and other respiratory diseases.
Children in this respect may be considered as a special risk group as they breathe more air relative to their body weight and lung surface, and thus receive proportionally higher doses of air pollutants systemically and locally. Furthermore children spend more time outdoor, and are more active, resulting in mouth-breathing and increased respiratory rate (see section 2).
Recently Jedrychowski et al. (1999) in a Polish study followed groups of children in two different areas, and over time compared their growth in lung function. They found a significantly greater growth in lung function among the boys from the area with low level air pollution compared to boys from the area with the higher air pollution level. For girls a similar difference did not reach the level of significance. The authors suggested that air pollution may lead to retardation in pulmonary function growth during the pre-adolescent years.
Several epidemiological studies indicate that children are susceptible to ambient air pollution. Increasing levels of ambient ozone levels have been shown to be associated with a decrease in lung function in children (Krzyzanowski et al. 1992, Hoek et al. 1993a, Hoek et al. 1993b, Braun-Fahrländer et al. 1994, Stern et al. 1994, Kinney et al. 1996).
In the study by Krzyzanowski et al. (1992), children together with asthmatics and adults spending long time outdoor were identified as having the most significant decline in lung function in relation to ozone exposure.
Burnett et al. (1994) studied the association between ambient air pollution levels and the number of daily hospital admissions at 168 hospitals in the Ontario area, representing 8.1 million people. Summer respiratory admissions were found to be closely related to ozone levels, and children was found to be especially affected as 15% of the admissions for children were associated with ambient air pollution compared with 4% for the elderly population.
Recently Loomis et al. (1999) and Woodruff et al. (1997) found increased infant mortality associated with ambient levels of fine particles. Loomis et al. (1999) found that a 10 m g/m3 increase in mean level of fine particles during a period of three days was associated with an 6.9% increase in infant mortality. The authors noted that this particle-related excess mortality observed among children was greater in relative risk terms than excess mortality observed among elderly people in several other studies.
In relation to average particle level (long term exposure) Woodruff et al. (1999) compared post-neonatal mortality in areas with different levels of air pollution. They found a significantly increased odds ratio of 1.10 for postneonatal mortality (adjusted for other covariates) in highly polluted areas compared to low pollution areas (mean particle levels of 44.5 µg/m3 and 23.6 µg/m3, respectively). The increased mortality was primarily due to respiratory-related mortality and sudden infant death syndrome. The authors suggested that children may be considered as a susceptible group in relation to particulate air pollution.5.4 Pesticides 5.4.1 Organophosphates
Organophosphorus insecticides are normally esters, amides, or thiol derivatives of phosphoric, phosphonic, phosphorothioic, or phosphonothioic acids. More than 100 different organophosphorus insecticides are known. Organophosphorus insecticides exert their acute effects in both insects and mammals by inhibiting acetylcholinesterase (AChE) in the nervous system with subsequent accumulation of toxic levels of acetylcholine (ACh), which is a neurotransmitter. Delayed neuropathy is initiated by attack on a nervous tissue esterase distinct from AChE. (WHO 1986a).
Many thousands of cases of acute poisoning by organophosphorus insecticides have been
recorded, the majority being due to parathion and methyl parathion (WHO 1986a).
The acute toxicity of different organophosphates ranges from highly toxic to only slightly toxic (oral LD50-values for the rat range from less than 1 mg/kg b.w. to over 3000 mg/kg b.w.) (WHO 1986a). Several studies have reported higher sensitivity based on lethality in young animals compared to adults following acute exposure to organophosphorus insecticides. The age-related differences in sensitivity may differ qualitatively and quantitatively with different organophosphates and varying exposure conditions (e.g., high vs. low dose, acute vs. repeated). A study by Liu et al. (1999) showed that repeated exposures to chlorpyrifos were associated with relatively similar degrees of cholinesterase inhibition among the age groups (neonatal, 7 days of age vs. adult, 90 days of age). In contrast, cholinesterase activity and muscarinic receptor binding were generally more reduced in neonatal relative to adult brain regions following repeated exposures to methyl parathion.
Many organophosphorus insecticides are embryotoxic at doses that are toxic for the
mother, but only few teratogenic effects have been reported (WHO 1986a).
In reproduction studies of methyl parathion at maternally toxic dose levels (ChE
inhibition), no consistent effects on litter size, number of litters, pup survival rates,
and lactation performance were observed; no primary teratogenic or embryotoxic effects
were noted. (WHO 1993b).
In USA, chlorpyrifos is one of the most commonly used pesticides in the indoor environment today. A recent study (Gurunathan et al. 1998) showed that after a single broadcast spraying of chlorpyrifos in the indoor environment, chlorpyrifos continued to accumulate on childrens toys and hard surfaces 2 weeks after spraying. Based on this study and other research studies, the estimated chlorpyrifos exposure levels for children from indoor spraying are approximately 20 to 120 times above the current recommended reference dose (US-EPA) of 3 g/kg b.w./day for chlorpyrifos exposure to children from all sources. (Davis & Ahmed 1998). In Denmark, pesticides are not used very much in the indoor environment (MST 2000 - personal communication).
A considerable number of reproduction and teratogenicity studies have been carried out with different carbamates and various animal species. Generally, the foetal effects included an increase in mortality, decreased weight gain in the first weeks after birth, and induction of early embryonic death. Certain carbamates also induce teratogenic effects, mainly at high dose levels applied by stomach tube. When the same dose levels was administered with the diet, no effects were seen. (WHO 1986b).
Lindane is the g -isomer of
1,2,3,4,5,6-hexachlorocyclohexane (HCH). Lindane interacts with cellular membranes and may
produce several generalised cytotoxic effects associated with impaired membrane function.
Paraquat is the dichloride salt of 1,1-dimethyl-4,4-bipyridinium ion.
Several drugs are known to induce various adverse effects in children including the unborn child. The classical example is the known human teratogen thalidomide which caused unusual limb defects in babies born of mothers who had taken thalidomide between the fourth and ninth weeks of pregnancy. A few other examples are given here.5.5.1 Chloramphenicol
Chloramphenicol is a broad-spectrum antibiotic having an antibacterial spectrum and
potency very similar to those of the tetracyclines. It is well absorbed from the
gastrointestinal tract, metabolised in the liver, and excreted rapidly in the urine
predominantly as metabolites. Chloramphenicol crosses the placenta and the concentration
in the foetus varies from 30 to 80% of the concentration in maternal blood.
Chloramphenicol is also secreted into the milk.
Chloramphenicol caused closure defects, among other abnormalities, in rats and non-specific malformations in rabbits. The teratogenic activity in the rat was attributed to interference with activity of the electron transport systems and oxidative energy formation in the embryo during embryogenesis. In mice and rhesus monkeys, no teratogenic effects have been noted under the regimens employed. Some postnatal behavioural effects, including reduction in learning ability, have been described in mice following prenatal treatment. (Schardein 2000c).5.5.2 Sulfonamides
Sulfonamides are derivatives of sulfanilic acid and used for treatment of
infections predominantly of the urinary tract. Only one sulfonamide, sulfamethizole, is
registered in Denmark.
One study of 458 women taking sulfonamides over the entire pregnancy reported that
there were more congenital malformations among their offspring than in the young of
untreated controls. Four other studies found no relation to sulfonamide therapy in early
pregnancy and malformations. A large collaborative study found no significant
malformations associated with the use of specific sulfonamides, including sulfamethizole.
DES is an artificial non-steroid oestrogen used as an antineoplastic agent for treatment of prostate cancer. DES is absorbed rapidly following oral administration, metabolised in the liver and excreted in the urine and faeces. (Lægemiddelkataloget 1996c, Schardein 2000e).
DES is a transplacental carcinogen in humans and development of adenocarcinomas in the
cervix and vagina have been observed in young females of mothers treated with DES during
5.6 Polychlorinated biphenyls (PCBs)
Because of their high persistence, and their other physical and chemical
properties, PCBs are present in the environment all over the world. The general population
is exposed to PCBs mainly through contaminated food (aquatic organisms, meat, and dairy
products). Infants are exposed through the mothers milk and it has been estimated
that the nursing period contributes about 1.3% of the life-time intake. (WHO 1993a).
In general, PCBs appear to be rapidly absorbed, particularly via the gastrointestinal tract after oral exposure; information on the rates of human absorption is limited. PCBs are rapidly cleared from the blood and accumulate in the liver and adipose tissue. There is evidence of placental transport, foetal accumulation, and distribution to milk. (WHO 1993a).
There are great difficulties in assessing human health effects separately for PCBs and
polychlorinated dibenzofurans (PCDFs) since, quite frequently, PCB mixtures contain PCDFs.
The Michigan Maternal and Infant Study has reported adverse developmental health outcomes in new-born infants of mothers who consumed more than 12 kg of contaminated Great Lakes fish. Statistically significant decreases in infants birth weight, gestational age, and head circumference compared to controls were observed. The infants also exhibited neurodevelopmental and behavioural deficits based on tests of visual recognition and memory at 7 months and 4 years of age. At 11 years of age, many of the neurobehavioural deficits had persisted, e.g., poorer short- and long-term memory and lower IQ scores. (Johnson et al. 1999).
Lesions induced in experimental animals exposed to PCB mixtures or individual congeners
concern the liver, skin, immune system, reproductive system, oedema, and disturbances of
the gastrointestinal tract and thyroid gland.
Consumption of food (including human milk) is the most important pathway for
exposure to PCDDs for the general population (adults and children) representing over 90%
of the total daily intake. Other pathways include inhalation and direct contact with
PCDDs. Exposure of infants and young children may be very high because of their relatively
high consumption of milk, including breast milk. (ATSDR 1998).
Humans can absorb PCDDs by the inhalation, oral, and dermal routes of exposure; absorption is vehicle-dependent and congener-specific. For most mammalian species, the liver and adipose tissue are the major storage sites of PCDDs. Tissue deposition is congener-specific and depends on the dose, the route of administration, and age; 2,3,7,8-substituted PCDDs are the predominant congeners retained in tissues. PCDDs are very slowly metabolised. The major routes of excretion are the bile and the faeces; smaller amounts are excreted via the urine. In mammalian species, lactation is an effective way of elimination PCDDs from the liver and other tissues. Human studies show that infants may absorb up to 95% of the amount ingested via breast milk. (ATSDR 1998).
A wide variety of effects have been observed in adults exposed to 2,3,7,8-TCDD. The
primary targets appear to be the skin, liver, thyroid, and cardiovascular, endocrine, and
immune systems; an increased cancer risk has also been observed. It is likely that these
organs/systems will also be sensitive targets in children. Children exposed to
2,3,7,8-TCDD appear to be more sensitive than adults to the dermal effects (chloracne). A
number of human studies have investigated the potential of 2,3,7,8-TCDD to induce
developmental effects. In one study, no significant increases in the incidence of birth
defects have been observed in the children of parents living in Seveso at the time of the
accident or during the next 6-year period. In contrast, other studies have found increases
in specific types of defects, although the total number of defects was not significantly
altered. (ATSDR 1998).
PBDEs are widely used in a variety of materials and products including textiles,
many types of electronic devices, cabins for and circuit boards in personal computers and
TV sets, electrical cables, switches and capacitors, and building materials. Furthermore,
PBDEs are found in several foods of animal origin (fish, meat, and cows milk)
(Darnerud et al. 1998, WHO 1994, WHO 1997b).
Studies on the reproductive toxicity of PBDEs are limited. Only one study on fertility
(decaBDE in rats) is available; no treatment-related effects in reproductive performance
or maturation of pups were reported.
A very recent study investigating possible neurobehavioural effects in neonatal mice (10 days old) following a single exposure to pentaBDE suggests differences in behavioural patterns between treated and control mice (Eriksson et al. 1998).5.9 Phthalates
Phthalates are high production volume chemicals widely used as additives in PVC plastics. Due to the ubiquitous use, phthalates are found everywhere in the environment.
In Denmark, the intake of the phthalates DEHP, DBP, and BBP has been analysed in a number of samples (29) from a double portion study where adults participated; estimates of the mean and maximum intake were 0.13-0.29, 0.02-0.03, and 0.19-0.3 mg/person/day for DBP, BBP, and DEHP, respectively. For children, the mean and maximum intake of phthalates from infant formulae has been estimated to <0.042, 0.0006-0.0009, and 0.009-0.021 mg/child/day (assumed child weight of 3 kg) for DBP, BBP, and DEHP, respectively. (Petersen 1999).
Some phthalates affect fertility and reproduction in rodents of both sexes and also produce developmental effects in the offspring.
Generally, phthalates with side chains of 4 to 6 carbons atoms in length, e.g.,
di-2-ethylhexyl phthalate (DEHP), dibutyl phthalate (DBP), and butyl benzyl phthalate
(BBP), affect the reproductive system of male rodents whilst phthalates with side chains
shorter than 4 carbon atoms and longer than 6 carbon atoms appear to be without effect.
Observed effects include marked reductions in the weights of the testes and accessory sex
glands, decreased numbers of spermatocytes, degeneration of the seminiferous tubules, a
reduction in testicular zinc and iron levels and serum testosterone levels, an increase in
testosterone levels in the testes, sloughing of germ cells, and vacuolisation of Sertoli
cells (DEHP). Spe cies differences have been observed as the reproductive system of the
male rat appears to be more sensitive than that of the mouse, which appears to be more
sensitive than that of the hamster, guinea pig, and non-human primates.
Numerous studies have shown that some phthalates induce embryotoxic and teratogenic
effects in the offspring. DEHP is embryotoxic and teratogenic in mice and embryotoxic in
rats at maternally non-toxic dose levels (CSTEE 1998, Nielsen & Larsen 1996). DBP
generally induce foetotoxic effects in rats and mice in the absence of maternal toxicity,
and teratogenic effects only at high maternally toxic doses (WHO 1997a).
In the non-smoking adult general population, the major exposure pathway for lead is
from food and water. The level of dietary exposure to lead depends upon many factors,
including foodstuffs consumed, processing technology, use of lead solder, lead levels in
water, and use of lead-glazed ceramics.
In humans, lead adversely affects several organ systems and organs, including the
nervous, haematopoietic, reproductive, and cardiovascular systems, the liver, the kidney,
and the gastrointestinal tract. Neurodevelopmental effects and subcellular changes,
particularly the effects on haem synthesis, appear to be the most sensitive endpoints.
Children, in comparison with adults, are more susceptible to lead in several respects. Children have a greater absorption of ingested lead than adults, resulting in a higher body burden from a given external exposure. About 40 to 50% of dietary lead is absorbed from the gastro-intestinal tract in infants and young children compared to around 5 to 10% in adults. Absorption of lead from ingested dust and soil is somewhat lower than from food, approximately 30% in infants and young children. It also appears that children are generally more sensitive to the toxicological effects of lead at a given internal exposure level (measured as the blood lead level) as the lowest observed effect levels (LOAELs) for various end-points (e.g. slowed nerve conduction velocity, impaired neurobehavioural function, encephalopathy, anaemia, reduced haemoglobin) are lower in children than in adults. (WHO 1995, WHO 1996).5.11 Mercury
The general population is primarily exposed to inorganic mercury and methyl mercury
through the diet. In most foodstuffs, mercury is largely in the inorganic form. Fish and
fish products are the dominant source of methyl mercury in the diet. Air and water can
also contribute significantly to the total daily intake of total mercury. Furthermore,
dental amalgam may also be a source of exposure to inorganic mercury due to release from
amalgam restorations. (WHO 1990, WHO 1991a).
Methyl mercury is a well-established neurotoxicant that can cause serious adverse effects on the development and function of the human central nervous system, especially when exposure occurs prenatally (Harada 1995). The neurotoxic potential was first described from industrial exposures as the Hunter-Russell syndrome, and then reappeared in the fishing town of Minamata, Japan, in the early 1950s (Igata 1993). Most surprisingly, while unaffected themselves by mercury toxicity, many pregnant women exposed to mercury-contaminated fish bore infants that suffered from severe congenital poisoning (Harada 1995, Igata 1993). The characteristics of this form of developmental neurotoxicity are now relatively well known at high exposure levels, where a cerebral palsy syndrome occurs. In less severe poisoning, blindness, deafness, and mental retardation may be apparent. In a poisoning incident in Iraq, a dose-response relationship was established between maternal hair-mercury concentrations during pregnancy and the prevalence of severe psychomotor retardation in the children (Marsh et al. 1990). This evidence from poisoning outbreaks clearly documents the hypersusceptibility of the developing nervous system with regard to this neurotoxicant.
Current concerns relate to the neurotoxic risks at lower exposure levels prevalent in fishing communities (Grandjean et al. 1997). A birth cohort of 1000 Faroese children was examined at age 7 years, where clinical examination did not reveal any clear-cut abnormalities associated with the cord-blood mercury concentrations. However, mercury-related neuropsychological deficits at this age occurred in the domains of language, attention, and memory, and to a lesser extent in visuospatial and motor functions. The associations could not to be explained by various possible confounders such as polychlorinated biphenyls (PCBs) from seafood, and they remained after exclusion of highly-exposed children with a maternal hair-mercury concentrations above 10 µg/g. This limit was thought to represent an upper safe level as based on the data from Iraq (WHO 1990).
Supporting evidence has now emerged from a fishing community in Madeira, where 149 children from the first grade in school showed mercury-related delays in the electrical signals of the brain, as recorded by the evoked potentials technique (Murata et al. 1999). A similar pattern was seen in the Faeroes (Grandjean et al. 1997). Other cross-sectional studies in Brazil (Grandjean et al. 1999) and French Guyana (Cordier et al. 1999), have shown mercury-associated developmental effects in agreement with the Faroese findings. However, a prospective study in the Seychelles has not revealed any clear adverse effects related to maternal hair-mercury concentrations, but results beyond 5 years of age are not yet available (Davidson et al. 1998).
Although the question as to the safety of fish consumption during pregnancy has not been settled, the preponderance of evidence indicates that the unborn child is much more susceptible to methyl mercury neurotoxicity than adults are. This substantial age-dependency may be a more general phenomenon for neurotoxicants, as similar evidence is available for other substances, especially lead and PCBs (Steuerwald et al. 2000).5.12 Copper
In the general population, the major route of exposure to copper is oral. Variations in dietary copper intake reflects different dietary habits as well as different agricultural and food processing practices used world-wide. In some cases, drinking water may make a substantial additional contribution to the total daily intake of copper, particularly in households where corrosive waters have stood in copper pipes. All other intake for copper (inhalation and dermal) are insignificant in comparison to the oral route. Women using copper-containing intra uterine devices (IUDs) are exposed to only minor amounts from this source. (WHO 1998a).
Copper is an essential element and adverse health effects are related to deficiency as
well as to excess intake. The relationship between intake and risk has a U-shaped curved,
with risk for deficiency associated with low intakes and risk for toxicity associated with
high intakes. The range of acceptable intakes which meet the biological requirement
without causing toxicity may be rather narrow.
The most frequent and appreciable general population exposures to boron are likely to be from ingestion of food and, to a lesser extent, from ingestion of drinking water. Other potential sources include absorption of boron from cosmetic and medical preparations through mucous membranes or damaged skin; and the inhalation, dermal absorption, or accidental ingestion of boron-containing household cleaning products, pesticides, or fertilisers. (WHO 1998b).
Boric acid is readily absorbed from the gastrointestinal and respiratory tracts. The absorption is essentially complete (approximately 95% in humans) following ingestion. Dermal absorption across intact skin is negligible in all species evaluated, including humans (infants and adults). Boric acid is rapidly excreted mainly (95%) by the kidneys. (WHO 1998b).
Only a few human studies have been conducted to assess health effects associated with
exposure to boron compounds, including boric acid.
After repeated oral administration to experimental animals, growth inhibition, organ
weight changes, and testicular damage are the most striking effects observed.
Nitrate and nitrite are naturally occurring ions that are part of the nitrogen
cycle. The nitrate ion is the stable form for oxygenated systems although it can be
reduced to nitrite by microbial action.
Ingested nitrate is readily and completely absorbed from the gastrointestinal tract and rapidly distributed throughout the tissues. Approximately 25% of ingested nitrate is actively secreted into saliva, where it is reduced to nitrite by the oral microflora. Bacterial reduction of nitrate may also take place in other parts of the human gastrointestinal tract. (WHO 1996).
The toxicity of nitrate to humans is thought to be solely the consequence of its reduction to nitrite. The major biological effect of nitrite in humans is its involvement in the oxidation of normal haemoglobin to methaemoglobin, which is unable to transport oxygen to the tissues. The reduced oxygen transport becomes clinically manifest when methaemoglobin concentrations reach 10% of that of haemoglobin and above; the condition, called methaemoglobinaemia and also known as the "blue baby syndrome", causes cyanosis and, at higher concentrations, asphyxia. The haemoglobin of new-borns and young infants is more susceptible to methaemoglobin formation than that of older children and adults. (WHO 1996).5.15 References
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