Reproductive Risks of Chemicals @ Work - EHSC Note - July 2006

Environment, Health and Safety Committee (EHSC) Note on Reproductive Risks of Chemicals at Work

20 July 2006

The purpose of this Note is to provide clarification of some of the complex and potentially emotive issues surrounding the subject of reproductive hazards, and hence risks, from chemicals at work. It is concerned only with known and suspected potential effects on human reproduction. The Note is not intended to provide data on individual chemicals; such information may be available from other sources. Reproductive hazards of chemicals at work are taken into account when the obligatory COSHH assessments are made. Legislation relating to the control of reproductive risks from chemicals at work merges into broader aspects of employment law which are not the subject of this Note. Furthermore where legislative considerations are mentioned these refer to the situation in the United Kingdom which is increasingly determined by developments at European level. This is a rapidly developing subject and the committee recognises that it may be necessary to revise this Note in due course in the light of new knowledge and legislative changes.

Reproductive Risks of Chemicals at Work

9 March 2006

http://www.rsc.org/images/Reproductive%20Risks%20Final_tcm18-54619.pdf
This Note was produced by a Working Party of the Environment, Health and Safety Committee [EHSC] of the Royal Society of Chemistry.
The Society is a registered Charity. Its Royal Charter obliges it to serve the public interest by acting in an independent advisory capacity. In order to meet this obligation the members of the EHSC are drawn from a wide range of backgrounds and serve on the committee as individual experts and not as representatives of their employer.
The EHSC welcomes comments on this Note.
Please send them to the committee secretary:
The Secretary Environment, Health and Safety Committee Royal Society of Chemistry Burlington House Piccadilly London
W1J 0BA
Tel: +44 (0) 207440 3337
Fax: +44(0) 207734 1227
Email: ehsc@rsc.org

NOTE ON REPRODUCTIVE RISKS OF CHEMICALS AT WORK

1. Introduction

The purpose of this Note is currently to provide clarification of some of the complex and potentially emotive issues surrounding the subject of reproductive hazards and hence risks from chemicals at work. It is concerned only with known and suspected potential effects on human reproduction. The Note is not intended to provide data on individual chemicals; such information may be available from other sources (see ‘Further Reading’).
Reproductive hazards of chemicals at work are taken into account when the
obligatory COSHH assessments are made.
Legislation relating to the control of reproductive risks from chemicals at
work merges into broader aspects of employment law which are not the subject of this Professional Brief. Furthermore where legislative considerations are mentioned these refer to the situation in the United Kingdom which is increasingly determined by developments at European level.
This is a rapidly developing subject and the committee recognises that it may be necessary to revise this Note in due course in the light of new knowledge and legislative changes.

2. General Considerations

The reproductive hazards of chemicals can affect men, women, the foetus and postnatal development. However such hazards have been demonstrated for relatively few chemicals and even fewer chemicals have been shown to be of high potency. A substance with reproductive toxicity is one that produces effects on the differentiation, development or adult functioning of the reproductive system. While caution in dealing with any chemical is always required there is no reason to think that reproductive hazards from exposure to chemicals at work are other than very small if proper precautions are taken.
As indicated above this Brief deals only with occupational exposure to chemicals and it must be recognised that there are many other potential
sources of exposure (e.g. “DIY”, gardening, domestic cleaning agents). This
Brief is not intended to cover substances deliberately administered for therapeutic purposes, although our knowledge of some reproductive effects has arisen in this way. Nor does this Note deal with ionising radiations or micro-organisms.
Reproductive hazards from chemicals have much in common with other forms of chemical toxicity (although in general there are less data). Thus harmful exposure is likely to occur only if substances are ingested, inhaled or absorbed through the skin in sufficient quantities. Similarly, “lifestyle factors” (e.g. diet and smoking) and genetic predisposition may affect any reproductive risk to an individual from a particular chemical. Also there is a natural background of reproductive abnormalities quite independent of any occupational chemical exposure.

3. Possible Reproductive Effects of Chemicals

The causes of adverse effects on the human reproductive process are very varied and, on the whole, poorly understood. Hereditary factors are usually accepted as being responsible for a large proportion of these effects. Environmental and “life-style” factors, including exposure to natural and synthetic chemicals, drugs, radiation and alcohol consumption are also contributors but the magnitude of each is unknown.
The following paragraphs seek to provide a brief outline of how the reproductive process works and some of the ways in which chemicals might adversely affect it. Some of the compounds for which there appears to be
evidence of an actual effect are mentioned.
Reproduction is a complex, multi-stage process covering all the events between the development of germ cells in both male and female, right through to the status of the offspring as a healthy sexually mature adult.
Interference at any of these stages may cause adverse effects, collectively described as “reproductive impairment”. Many associations between chemical exposure and reproductive effect are based on limited evidence. There is extreme difficulty in many cases in developing satisfactory cause and effect relationships. Estimates of the extent of particular influences may vary widely from source to source.
In general, reproductive efficiency in men and women decreases with age. It is difficult to estimate the overall rate of reproductive impairment in the “normal” human population. This is because figures quoted for specific types of impairment are often incomplete and in particular, because most spontaneous abortions occur very early and may be perceived as late menstruation. However the following estimates have been suggested for a “developed” society:
• 10 to 15% of couples are clinically infertile
• more than one-third of early human conceptions and 10 to 15% of recognised pregnancies are terminated by spontaneous abortion usually between the 7th and 12th weeks of pregnancy.
On the basis of abnormalities recognised during the first year of life it is estimated that up to 8% of newborn babies have behavioural, functional or morphological birth defects (see March of Dimes Birth Defects
Foundation www.marchofdimes.com). Around one out of every 28 babies has some type of birth defect. That is an abnormality of structure, function or metabolism present at birth that results in physical or mental disability, or is fatal. Birth defects are the leading cause of death in the first year of life. Both genetic and environmental factors can cause birth defects although the causes of about 60 to 70% are currently unknown.
A relatively small number of chemical, physical and biological agents have been linked to specific effects but the cause of most reproductive impairment remains unknown. Of all the chemical substances and mixtures which are commercially available few other than drugs, pesticides, food additives and new industrial chemicals have been evaluated for reproductive effects.
In the main adverse effects have been identified by direct practical experience from either accidental occupational exposure or as side effects of therapeutic drugs. Thalidomide is the classic example. Exposure is often difficult to identify, as for example with diethylstilboestrol, or quantify and of course, once discovered or suspected, cannot be subject to experimental examination. Experimental animal studies on the other hand, have identified a number of unrelated chemicals that cause adverse reproductive effects of various sorts.
While these results are likely to be used, for regulatory purposes, to indicate a potential hazard, the predictability of risk to humans arising from exposure to these substances is much more limited because animal models often do not mimic the relevant human biology. There are considerable differences in
absorption, metabolism and genetic variability between humans and other species. However, advances in toxicogenomics and other –omics are increasing our knowledge of the mechanisms that cause reproductive toxic effects.
It is against this background that the general question of the reproductive hazards of chemicals must be set.
Earlier studies focused mainly on the possible association between exposure of the mother to chemicals during pregnancy and subsequent birth defects, especially anatomical abnormalities in the offspring (vide infra – thalidomide and diethylstilboestrol). More attention is now paid to effects resulting from exposure of either parent at other stages of the reproductive process.
Reproduction may be subdivided into germ-cell development, pre-natal and postnatal stages. For ease of presentation reproductive hazards may be considered in terms of possible end points in these various stages.

Toxic effects on the human male reproductive system
Some examples of chemicals which have been implicated in affecting the human male reproductive system are:
• the nematocide DBCP (1, 2-dibromo-3-chloropropane) (infertility)
• kepone and carbon disulphide (reduced sperm counts)
• lead (sperm abnormalities)
• 1, 2-dibromoethane (reduced fertility)
In addition mention must be made of substances which are not normally thought of as “chemicals”. Alcoholic drink is a well-known cause of impotence in men and reduced sperm counts have been imputed to marijuana smoking.
Finally, compounds with oestrogenic (feminizing) effects may interfere with the reproductive process by reducing libido.

Toxic effects on the human female reproductive system
Toxic chemicals that target the female reproductive system can cause a wide variety of adverse effects.
Changes in sexual behaviour, onset of puberty, cyclicity, fertility, gestation time, pregnancy outcome, and lactation and premature menopause. All these adverse effects can disrupt a woman’s ability to reproduce successfully.

Some examples of chemicals which have been implicated in affecting the human female reproductive system are:
• Lead - menstrual disorders and infertility.
• Carbon disulphide, mercury, and polychlorinated biphenyls (PBCs) - cause irregularities in the menstrual cycle.

Toxic effects in the pre-natal and perinatal periods
The pre-natal period comprises pre-implantation, embryonic and foetal stages. The preimplantation phase lasts about two weeks and chemical toxicity at this stage usually leads to the death of the developing
organism so that an abnormal foetus does not develop. The next phase when the basic development of organ structures takes place lasts broadly from days 20 to 55. This is a period of particular vulnerability to insults leading to morphological defects. These may be severe enough to cause embryonic death or may be manifest at term as birth defects. Within this general developmental timescale individual organ systems have their own
periods of particular vulnerability and these have been well documented. After the 7th or 8th week of pregnancy the major processes are tissue development, functional maturation and continuing growth. Toxic effects during this period may lead to retardation of growth or functional disorders. The foetus (i.e. after 7-8 weeks) is more resistant to lethal effects than the embryo but severe toxic chemical insults can lead to stillbirths. Thus the most important phase of pregnancy for induction of birth defects may be before the pregnancy is recognised.
The placenta prevents the passage of some substances to the foetus and acts to metabolise other chemicals absorbed by the mother. The end products of this metabolism are usually less toxic than the original compounds but this is not invariably so and some chemicals may be activated to more toxic metabolites. The development in the foetus of enzyme systems for metabolizing foreign chemicals is slow and is not complete till after birth. Examples of materials which may exert toxic effects in this pre-natal phase are methylmercury
compounds (CNS effects) and some heavy metals (embryotoxic).

The best known examples of developmental toxicants are:
• thalidomide prescribed for morning sickness which, taken in the first trimester, caused gross malformations (largely shortening)of limbs and ears.
• diethylstilboestrol (DES) which was prescribed to pregnant women to prevent miscarriage. It was also used to stop breast milk and to inhibit growth in young girls. It was subsequently found to cause clear-cell adenocarcinoma of the vagina and cervix in women exposed in utero. Also, DES increases the risk of
testicular cancer in males exposed in utero.

Other substances known to be teratogenic in humans include:
• Alcohol: heavy alcohol consumption by pregnant women is associated with adverse effects upon offspring. Known as the foetal alcohol syndrome, this is characterised by facial, limb and cardiovascular abnormalities, growth retardation and CNS dysfunction,
• Angiotensin converting enzyme inhibitors (ACE Inhibitors) (captopril, enalapril, lisinopril) are potent antihypertensive drugs associated with, interalia, foetal toxicity including intrauterine renal insufficiency.
• Cigarette smoking is associated with low birth weight, shortened gestation and increased perinatal mortality have been attributed to
• Cocaine use during pregnancy has been associated with abruptio placentae, prematurity, foetal loss, decreased birth weight, microcephaly, limb defects, urinary tract malformations, and poorer neurodevelopmental performance.
• Hydantoins (phenytoin and trimethadione) have been associated with a recognisable pattern of malformation termed the foetal hydantoin syndrome. The clinical features include craniofacial dysmorphology.
• Lithium poses a higher risk for major anomalies than in the general population and a specific risk for cardiac teratogenesis in early gestation.
• Tetracyclines may produce yellow-brown discolouration of teeth
• Valproate in the first trimester is associated with, inter alia, neural tube defects. Compounds which may be teratogens include: D-penicillamine, Methimazole and Diazepam

Toxic effects in the postnatal period
Development of the nervous, immune, endocrine, reproductive and metabolising systems continues after birth.
Some chemicals absorbed by the mother are excreted in breast milk, unchanged or as metabolites. Hence the opportunity for toxic insult to the new-born baby by those chemicals is significant following sufficient exposure.
Heavy metals, PCBs and PBBs have all been associated with this route of exposure.

4. Conclusions

The identification of the reproductive effects of chemicals and their dose-effect relationships is in many respects a rapidly developing science. However it has many features in common with other forms of chemical toxicity. Detailed assessment of risk requires reliable, high quality data covering population exposure and outcome. Except in a very few cases such data are not available.
Reproductive hazards are only one of the potential risks to health that have to be controlled in the workplace.
In general it is desirable that legislation to control the use of chemicals at work should so far as is practicable protect inter alia against adverse reproductive effects.
Women of child-bearing age are often considered a group of particular concern in relation to chemical reproductive hazards requiring special provisions. However it is clear from the information above that the possibility of adverse pre-conception effects exists at any time in either sex, and not just during pregnancy.
More importantly there may be adverse effects before pregnancy is recognised. It is thus important that, as far as practicable, adequate protection be afforded to all persons at risk at work. This must be a standard feature
of all COSHH hazard assessments, as set out in the HSE publication “COSHH Assessments; a step-by-step guide to assessment and the skills needed for it”. Where appropriate occupational exposure limits should be set so as to take account of known reproductive effects.
For additional reassurance some organisations offer pregnant employees the opportunity to work away from chemicals during part or all of their pregnancy, but clearly this should be in addition to the above safeguards.
Except for those chemical groups where there are regulatory requirements for reproductive toxicity testing (e.g. pharmaceuticals, pesticides, new bulk industrial chemicals) there is a shortage of information on reproductive effects of most substances. It is to be hoped that advances in knowledge will lead to a better understanding of which chemicals may affect reproduction, and of the relevant dose-response relationships and hence to a consequent improvement in risk assessment and control.

5. Glossary

CNS central nervous system
COSHH Control of Substances Hazards to Health Regulations
FSH follicle-stimulating hormone
Germ-cell any of the embryonic cells that have the potential to develop into spermatozoa or ova
Hazard a hazard is something with the potential to cause harm
HSE Health and Safety Executive
LH luteinizing hormone
Oocyte an egg-cell in the ovary that undergoes division to form an ovum
Oogenesis process by which mature ova are produced in the ovary
PBB polybrominated biphenyl
PCB polychlorinated biphenyl
Risk a risk is the likelihood of a hazard being realised
Teratogen an agent that has the potential to cause birth defects through interference with normal embryonic development if exposure to the foetus occurs at a critical time in pregnancy.

6. Further Reading

Casarett and Doull's Essentials of Toxicology 2003 Klaassen C D, Watkins J. McGraw-Hill Publishing Co.
512 pages ISBN: 0071389148

Principles and Methods of Toxicology 2001 4th ed. Hayes AW Ed. Taylor & Francis Inc.912 pages ISBN: 1560328142

International Programme on Chemical Safety 2001 Environmental Health Criteria No. 225. Principles for evaluating health risks to reproduction associated with exposure to chemicals.
http://www.inchem.org/documents/ehc/ehc/ehc225.htm

March of Dimes http://www.marchofdimes.com

Schardein J L. 2000 Chemically Induced Birth Defects, 3rd ed. New York: Marcel Dekker, Inc., xiv, 1109 pages, ISBN 0824702654

This Note was prepared by a Working Party of the RSC Environment, Health and Safety Committee [EHSC].
The members of the Working Party were:
Dr I Wrightson [Chairman]
Dr C Grundy
Ms M George
Dr J Hoskins
Dr N King
Dr D Lohmann
Dr G McHattie
Mr D Sanderson
Mr P Whitehead
Dr S Lipworth [Secretary]

Contact
Dr Steven Lipworth
Health, Safety and Environment Officer
Royal Society of Chemistry, Burlington House, Piccadilly, London W1J 0BA, UK
Tel: +44 (0) 20 7440 3337
Fax: +44 (0) 20 7734 1227
Email: Dr Steven Lipworth