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What GPs should know about man-made chemicals

In modern society

we are exposed to thousands of man-made chemicals in our lives. Most of us have measurable levels of at least 300 groups of chemicals in our bodies, taken in through food, household chemicals, cosmetics, garden chemicals and even the air we breathe. When the groups of organic chemicals are broken down into their individual variants it transpires we are challenged by a mixture comprising tens of thousands of different compounds, some of which are potentially harmful.

Evolution and toxicology

Certain groups of chemicals have not appeared in the mainstream of evolutionary development (for example, no organochlorine compounds occur naturally in any vertebrate species). The reasons are unclear, but the point is obvious: if anthropogenic organic chemicals which are not part of normal biochemistry are introduced in bulk into the environment, harmful effects should be anticipated. This means that any regulatory risk assessment regime should address the impact of long-term, low-dose exposure on the most vulnerable members of society (usually the fetus and infant).

The complexity of influences on human pathology makes it difficult to prove causal relationships between exposure to chemicals and disease. Yet there are worrying changes in the pattern of human disease.

Hormonal disruption

An implicit assumption has been made that man-made organic chemicals can be assessed solely on their physical and chemical properties, supplemented by some simple acute high-dose toxicity testing before they are produced in large quantities. Bulk chemicals, particularly 'low volume' products, still have relatively little testing, despite the fact that their toxicological impact might be high. Indeed, for the majority of chemicals, there is currently little or no toxicological information. I believe this has proved to be a costly mistake whose legacy will persist for many generations to come. In contrast, acute, sub-acute, chronic and reproductive toxicity tests in animals are routine for pharmaceuticals and agrochemicals.

A significant proportion of the chemicals to which we are exposed in our everyday life can disrupt the endocrine system, causing many potential health effects. Most of these chemicals cross the placenta or may be passed to the newborn via breast milk.

Synthetic chemical molecules can 'disrupt' hormones in a number of ways. By chance similarities with a natural hormone, they can dock with the receptor and produce an effect (mimicry). Others dock with the receptor and produce no effect but competitively block the access of natural hormones to the receptor site.

Hormone-disrupting chemicals can also interfere with hormone synthesis, secretion, transport, degradation or excretion. Our knowledge of the structure-function relationship between hormones and their receptors is not yet advanced enough to be able to predict the likely hormone-disrupting properties of a novel chemica · 1. We therefore have to rely on bioassays to detect such properties2. In nature, it is very rare for chemicals to bioaccumulate. This is not necessarily true of synthetic bulk chemicals, and many of those few tested are persistent and do bioaccumulate.

Bioaccumulation is considered in the development of drugs. In the USA (but not yet in Europe), ecotoxicological testing is now being applied to pharmaceuticals. Additionally, toxic metabolites are also looked for in medicines. Environmental bioaccumulation and biomagnification have been tested in new agrochemicals for a number of years. For bulk chemicals, no such testing was performed in the past, and even now testing is very limited. Some persistent organic pollutants are being phased out but only minimal attempts have yet been made to deal with the major problem of unwanted by-products such as dioxins.

Pharmaceuticals are normally tested in combination with other drugs that might have synergistic or antagonistic effects. The problem is certainly considered. In addition, doctors are briefed on the possible negative side-effects of drugs and therefore are vigilant to detect them. For chemicals in the environment, nothing is known beforehand and action only currently occurs after a high-dose disaster or the appearance of a new illness.

The main defence in debating the health effects of everyday chemical exposures is that there is insufficient evidence of effect. This is hardly surprising, given the lack of baseline health studies and exposure information.

In addition, chemicals are tested singly, but they act in the body in a complex mixture. If thalidomide had caused cleft palate instead of phocomelia it is quite likely that we still would not know, because cleft palate is relatively common. The chance of finding causal relationships between components of a complex mixture and changes in the incidence of a common disease (such as cancer) is virtually zero.

Toxicologists are quite good at detecting, measuring and quantifying the toxicity of a single substance or even at working out the interaction between two known toxic substances. When it comes to studying complex mixtures, we do not yet have adequate tools to measure all interactions3. Those few combinations of chemicals that have been tested for their combined effect often produce a greater than predicted combined effect4,5.

There are around 70,000 chemicals currently in commercial use, with about 1,000 new ones added each year. The prospect of testing the toxicity of this many different chemicals, even singly, is daunting. But to test just the commonest 1,000 toxic chemicals in unique combinations of three would require at least 166 million experiments (ignoring the need to study varying doses6,7).

Effects of chemicals on health

The oestrogenic, anti-oestrogenic and

anti-androgenic nature of many chemicals in the environment has been linked with many effects in humans and animals2,8. Health effects which have been demonstrated to be connected with generally prevalent levels of dioxins and PCBs, include neurobehavioural, immune and reproductive system deficits9-17.

Take a single example: most current medical textbooks state that 1 per cent of girls will display signs of puberty before the age of eight, as defined by breast development or the appearance of pubic hair. One study in the USA found 1 per cent of all girls are now presenting with one or both signs by the age of three. By the age of eight, some 48.3 per cent of African-American and 14.7 per cent of white American girls (presenting at clinics rather a randomised sample) had developed signs of puberty18.

Another US study measured PCBs and DDE (a hormonally active metabolite of DDT) between 1979 and 1982 in blood and breast milk of hundreds of pregnant women and also in the umbilical cord blood after birth. In 600 of these children, girls with a high fetal exposure to PCBs and DDE entered puberty on average 11 months earlier than the others19.

A recent study20 measured the levels of phthalates (about three million tonnes a year used principally to soften PVC) in Puerto Rican girls with thelarche (precocious breast development). Phthalate levels were raised in 68 per cent of girls presenting with thelarche, while only one control subject.

It is not possible to completely define the causes for this evident decrease in the onset of puberty in girls. Nor can we predict the neurobehavioural development of girls who are developing breasts as young as 23 months of age, or the longer-term health implications. However, these developments are obviously undesirable.

How can exposure be reduced?

A precautionary approach would be to reduce human exposure to all chemicals which persist and bioaccumulate or are capable of hormonal disruption, down to the absolutely unavoidable level. For most of the known hormone-disrupting chemicals, there are substitutes which are less obviously problematic. The main rationale for continuing the status quo appears to be predominantly financial.

On an individual basis, we can reduce our exposure by eating organic food whenever possible, and avoid using cosmetics, furniture, flooring, pesticides, fungicides and household cleaners formulated with harsh chemicals, turning instead to the many environmentally friendly alternatives that are now available.

Dr Vyvyan Howard explains how artificial chemicals can disrupt hormones and what can be done to avoid this

Key points on toxicology

 · Harmful effects should be anticipated from chemicals that do not naturally occur in human biochemistry

 · Chemicals can disrupt hormones by 'blocking' or 'mimicking' receptors

 · Bulk chemicals are not routinely rigorously tested for harmful effects

 · Rigorous testing is very difficult to achieve due to the thousands of chemicals and mixtures produced

 · Chemicals such as DDE and phthalates have been implicated in hormonal problems in studied populations

 · Individuals can help themselves by using environmentally friendly chemicals

References

01 McLachlan JA. Functional toxicology: a new approach to detect biologically active xenobiotics. Environ Health Perspect 1993;101:386-7

02 Sonnenschein C, Soto A. Reflections on bioanalytical techniques for detecting endocrine disrupting chemicals. In: Nicolopoulou-Stamati P et al. (eds), Endocrine Disrupters: Environmental Health and Policies. 2001: Kluwer Academic Publishers, 21-38

03 Howard CV. Synergistic effects of chemical mixtures - Can we rely on traditional toxicology? The Ecologist 1997;27,192-5

04 Axelrad JC et al. Interactions between pesticides and components of pesticide formulations in an in vitro neurotoxicity test. Toxicology 2002;173:259-68

05 Rajapakse N, Silva E, and Kortenkamp A. Combining Xenoestrogens at Levels below Individual No-Observed-Effect Concentrations Dramatically Enhances Steroid Hormone Action. Environ Health Perspect. 2002;110:917-21

06 Lang, L. Strange brew: assessing risk of chemical mixtures. Environ Health Perspect 1995 103,142-5

07 Orkin M, Drogin R. Vital Statistics. New York: McGraw-Hill, 285, 1975

08 Kelce WR et al. Persistent DDT metabolite p,p'-DDE is a potent androgen receptor antagonist. Nature 1995;375,581-5

09 Toppari J et al. Male reproductive health and environmental chemical xenoestrogens. Environ Health Perspect 1996;104(S4):741-803

10 Swann, SH et al. The question of declining sperm density revisited: an analysis of 101 studies published 1934-1996. Environ Health Perspect. 2000;108, 961-6

11 Koppe JG et al. Background exposure to dioxins and PCBs in Europe and the resulting health effects. In: Nicolopoulou-Stamati P et al. (eds) Health Impacts of Waste Management Policies. 2000: Kluwer Academic Publishers, 135-154

12 Koppe J, De Boer P. Immunotoxicity by dioxins and PCBs in the perinatal period. In: Nicolopoulou-Stamati P et al. (eds), Endocrine Disrupters: Environmental Health and Policies. 2001: Kluwer Academic Publishers, 69-80

13 Lanting, C.I. Effects of Perinatal PCB and Dioxin Exposure and Early Feeding Mode on Child Development. PhD Thesis, Enschede: Printpartners Ipskamp B.V., 1999

14 Weisglas-Kuperus N et al. Immunologic effects of background exposure to polychlorinated biphenyls and dioxins in Dutch preschool children. Environ Health Perspect 2000; 108:1203-7

15 Duty S et al. The relationship between environmental exposures to phthalates and DNA damage in human sperm using the neutral comet assay. Environ Health Perspect 2003. Online Preprint 6 December 2002 doi:10.1289/ehp.5756

16 Patandin S et al. Effects of environmental exposure to polychlorinated biphenyls and dioxins on cognitive abilities in Dutch children at 42 months of age. J Paediatr 1999;134:33-41

17 Vreugdenhil HJ et al. Effects of perinatal exposure to PCBs and dioxins on play behaviour in Dutch children at school age. Environ Health Perspect 2002;110:A593-8

18 Herman-Giddens ME et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings Network. Pediatrics 1997;99:505-12

19 Boyce N. Growing up too soon. New Scientist 1997;2093:5

20 Colón, I et al. Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development. Environ Health Perspect 2000;108:895-900

Examples of alternative substances readily available

 · PVA (polyvinyl alcohol) plastics instead of PVC

 · Linoleum or ceramic instead of vinyl flooring

 · Peroxide bleach instead of chlorine bleach (in toiler cleaner, dishwasher tablets, laundry products etc)

 · Natural antiseptics (such as tea tree or lavender oil) instead of chlorine-based antiseptics such as TCP

 · Toothpastes, soaps, cosmetics based on natural products, avoiding bactericides such as triclosan (a polycyclic organochlorine) and artificial perfumes

 · Fruit juice and cordials in glass or non-chlorinated plastic bottles (the recycling stamp on bottle gives the type of plastic)

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