Chemicals and public health
An information brochure on the assessment of toxicity
31 December 2004
Chemicals and Public Health
The widespread use of chemicals and their presence in food and in the environment is of concern to many people who believe that exposure to these chemicals may be associated with health problems. This brochure explains in general terms, firstly, how public health is protected through the study of the toxicity of chemicals and their potential to cause adverse effects on humans; and secondly, how this information is used in the development of exposure standards to ensure that there is little if any health risk as a result of the use of most chemicals. The focus of this brochure is on agricultural and veterinary chemicals, but for more detailed information, and for information on assessment of other types of chemicals, the reader is referred to the relevant authorities listed at the end of the brochure.
What is toxicity?
The toxicity of a chemical is its capacity to cause adverse health effects. It applies to both synthetic and naturally occurring chemicals. The nature and extent of any adverse effect in humans and animals will depend on the level and length of exposure to the chemical, and whether it is taken orally, absorbed though the skin or inhaled.
Why study the toxicity of chemicals?
Every day people are exposed to a wide variety of chemicals, and the toxicity of these chemicals needs to be studied to identify potentially harmful effects and to establish acceptable levels of exposure.
Exposure to a chemical can be brief, such as the occasional use of a paint stripper or garden weedkiller, or prolonged, such as the ingestion of an additive or pesticide residue in food, or by breathing a contaminated atmosphere. Human safety is of central importance in each of these situations.
On which chemicals are toxicity studies performed?
Toxicity studies are commonly performed on chemicals that have the potential for significant public exposure, but the extent of testing varies depending on the chemical type and the expected level of human exposure. For instance, agricultural chemicals, food additives, human medicines and veterinary drugs undergo thorough toxicity testing because of the extent of their use, and the potential for human exposure to, such chemicals. Veterinary drugs are also studied to determine their safe use in the animal species on which they will be used. However, requirements may vary for chemicals that have limited public exposure or restricted uses, such as some industrial chemicals. This flexibility of requirements allows for an appropriate level of toxicity testing for a particular exposure situation.
What types of toxicity studies are carried out?
The extent and type of studies required for a particular chemical depends on its proposed use and the likely extent of human exposure. Therefore studies range from measuring short-term effects to those that examine the effects of life-time exposure, but not all of these studies are required for the regulation of all types of chemicals. The specific studies required to register agricultural and veterinary chemicals are listed in two separate volumes entitled Guidelines for Registering Agricultural Chemicals and Guidelines for Registering Veterinary Chemicals. These volumes are available from the Australian Pesticides and Veterinary Medicines Authority (APVMA).1 The study requirements for industrial chemicals are available from the National Industrial Chemical Notification and Assessment Scheme <http://www.nicnas.gov.au>.
1. Formerly the National Registration Authority (NRA)
Toxicity studies are generally performed on laboratory animals that include mice, rats, guinea pigs, rabbits, dogs and occasionally primates. They are designed to provide information about how the test chemical is absorbed, metabolised and excreted, and to identify potential toxic effects in a broad range of situations. The studies generally involve giving animals various doses of the compound under investigation, usually by feeding, dermal application or inhalation, followed by observation and numerous measurements to indicate the extent, if any, of toxicity. Generally, signs of immediate toxicity are relatively easily observed such as from acute poisoning or from skin and eye irritation. The effects of long-term, low-level exposure, however, may be more difficult to determine without more sophisticated examinations, as the lack of immediate clinical signs is not necessarily an indication of a lack of toxicity.
The short-term hazard from a chemical is determined by identifying the acute toxicity by the most likely routes of exposure, together with tests for skin and eye irritation, and skin allergy. The effects of repeated exposure to the chemical, taken orally, absorbed through the skin or by inhalation, are also investigated. The potential for toxic effects over longer periods, including cancer, is determined by studying lifetime exposure to chemicals, usually through the diet. Multi-generation and developmental studies predict reproductive toxicity and the potential to cause birth defects. Further studies are performed to assess the potential to cause genetic effects that may lead to heritable defects or the development of cancer.
Other specific studies also may be required to clarify the detailed mechanism of toxicity of a particular chemical, for example the effects on the brain or the immune and nervous systems. In addition, data from well-conducted studies in human volunteers may also be used to assess the risk of a chemical, providing such studies meet strict national and international ethical standards. However, such studies are not a requirement for assessment of agricultural and veterinary chemicals in Australia.
Why do toxicity studies need to involve animals?
Although there is increased worldwide use of non-animal systems for studying the toxicity of chemicals (ie. in vitro tests using cell or tissue culture techniques) they do not reproduce all the complex interactions between chemicals and animals. Consequently, laboratory animals continue to be used as models for humans, supplemented with information from some in vitro assays. Toxicity studies must comply with strict national guidelines on animal ethics and international guidelines such as the OECD Guidance Document on the Recognition, Assessment and Use of Clinical Signs as Humane Endpoints.
Currently, it is unlikely that non-animal testing will replace the use of laboratory animals, although research may lead to better in vitro tests to complement studies in vivo, and thus fewer animals being used. Indeed, many chemical companies use non-animal tests, although not validated by regulatory authorities, to screen potential new substances.
Who performs the studies?
The company that intends to market the chemical in Australia is responsible for providing adequate toxicity studies to allow assessment agencies to determine the safety of the chemical. These are done in the company's laboratories or under contract in private testing facilities. The studies must be performed in compliance with agreed international standards of quality (Good Laboratory Practice). Because of the costs of facilities and personnel needed to meet these guidelines, few such studies are performed in Australia, but where they are conducted, these laboratories are subject to regular Government inspection.
Toxicity studies are also performed under the direction of international organisations such as the International Agency for Research on Cancer, or government agencies such as the US National Toxicology Program.
Who is responsible for public safety of chemicals?
The regulation of chemicals in Australia is generally divided between national (Australian Government) schemes for assessment or registration, and regional (States and Territories) schemes that focus on managing the effects of chemicals by control of use and monitoring programs. To achieve uniformity between States, appropriate standards and/or guidelines for maximum allowable exposure limits, product labelling, maximum residue levels in food, and poisons scheduling are developed at the national level for incorporation into State legislation. The States operate through a variety of legislation that regulates poisons, pollution, food quality and water quality. For example, Food Standards Australia New Zealand (FSANZ) develops the Food Standards Code for adoption by the States.
Who evaluates the study results?
The Office of Chemical Safety of the Therapeutic Goods Administration (TGA), which is part of the Department of Health and Ageing, reviews and interprets the toxicology data on agricultural and veterinary chemicals, and provides advice on public health and occupational health and safety (OHS) issues to the APVMA. It also provides advice on appropriate standards for public health exposure to the Department, the National Health and Medical Research Council, other Commonwealth and State Government agencies, and to the public. FSANZ is responsible for assessing the toxicology data on food additives and contaminants. Industrial chemicals are assessed by NICNAS, which is also within the TGA Group of Regulators. NICNAS also assesses chemicals used in cleaning products, cosmetics and toiletries. Other areas of the TGA evaluate the safety, quality and efficacy of therapeutic goods, including prescription, non-prescription, and complementary medicines. For agricultural and veterinary chemicals, additional advice on public health issues is also provided to the TGA by expert advisory committees, which contribute to the decision-making and peer-review processes for some public health issues on chemicals.
More details on the agencies involved in various National Chemicals Assessment and Registration Schemes are outlined in a separate document, Assessment & Registration of Chemicals in Australia, which can be obtained from the assessment agencies listed at the end of this brochure, or on the NICNAS website <http://www.nicnas.gov.au/Chemicals_In_Australia.asp>.
How are the results of toxicity studies used to assess public safety?
Toxicity studies on laboratory animals help us to understand how a chemical may cause health problems in humans. However, whilst such studies are usually predictive of effects in humans, toxic responses can vary between animal species because of biochemical, physiological or anatomical differences, and the results in animals may not always be applicable to humans. Toxicity studies in animals are carried out over a range of dose levels to produce a gradation of toxicity and, if possible, to identify a basis for those effects and a dose at which no effects occur. The results of the various studies must be reviewed and evaluated before public health risks can be assessed.
Data from toxicity studies, particularly acute studies, together with information on the properties of the chemical are used to propose warning statements, safety directions, general safety precautions and first-aid instructions related to the use of the chemical. These statements are included on the label of the chemical container. Another control mechanism used to reduce the likelihood of poisoning is implemented through scheduling of substances, eg. restrictive scheduling limits public access to products containing highly toxic substances.
Data from long-term, reproduction and developmental toxicity studies enable safe levels to be determined for lifetime exposure to additives, contaminants, or pesticide residues in food. The acceptable daily intake (ADI) for humans is considered to be a level of intake of a chemical that can be ingested daily over an entire lifetime. It is calculated by applying a safety factor (usually 100 or more) to the dose level which causes no effect (called the NOEL or no-observed-effect-level) in the most sensitive animal species. The safety factor is selected to account for uncertainties in using animal data to predict effects in humans, the adequacy of the available data, variation between different individuals, and the nature of the potential adverse effects. For example, where animal studies indicate that there is a risk of a serious effect from a particular chemical, such as birth defects, a larger safety factor may be applied to minimise any risk to humans. The Australian ADI list for pesticides is available on the Australian Government Department of Health and Ageing website <http://www.health.gov.au/internet/main/publishing.nsf/content/ocs-adi-list.htm>.
Data from toxicity studies which investigate effects (including potential developmental effects) after one or a few doses enable safe levels to be determined for single (or acute) exposure to additives, contaminants, or pesticides. The acute reference dose (ARfD) for a chemical is considered to be the amount that could be ingested in a single meal or over a day without any health effects being apparent. The ARfD is formally defined as "an estimate of the amount of a substance in food and/or drinking water, normally expressed on a body weight basis, that can be ingested in a period of 24 hours or less, without appreciable health risk to the consumer, on the basis of all the known facts at the time of the evaluation". It is calculated in a similar manner as the ADI, by applying a safety factor to the NOEL for acute effects in the most sensitive or appropriate animal species. The Australian ARfD list for pesticides is available on the Australian Government Department of Health and Ageing website <http://www.health.gov.au/internet/main/publishing.nsf/Content/ocs-arfd-list.htm>.
Maximum residue limits (MRLs) are the maximum concentration of a chemical residue in or on a food, agricultural commodity, or animal feed, resulting from the registered use of an agricultural or veterinary chemical. The MRL Standard is available on the APVMA website <http://www.apvma.gov.au/residues/mrl.shtml>. The APVMA sets these MRLs at levels that should not be exceeded if the agricultural or veterinary chemicals are used in accordance with approved label instructions. The MRLs set by the APVMA for human foods are advanced to FSANZ for incorporation into the Food Standards Code. FSANZ uses national dietary survey data to ensure that persons consuming food that contains the MRL are unlikely to receive greater than the ADI for that chemical. The Food Standards Code is available on FSANZ's website <http://www.foodstandards.gov.au/thecode/>.
How are standards for studies maintained and upgraded?
Studies are generally performed using methods developed by member countries of the OECD (Organisation for Economic Co-operation and Development) or the United States EPA. As scientific knowledge increases, guidelines for conducting such studies may change, as may the principles for their interpretation.
Australian regulatory agencies maintain an awareness of developments in toxicology in a number of ways, eg. contribute to international chemical review processes, participate in activities aimed at international harmonisation of assessment reports and methodology, and the development of toxicology test guidelines. As a consequence, assessment reports from Australian agencies are considered to have achieved a high standard and are sought after for use by regulatory agencies in other countries.
Can current toxicity studies predict all potential human health effects?
No amount of understanding of the toxicity of a chemical can predict an individual's response to a specific chemical in all situations. Toxicity studies can, however, provide information that can be used to significantly reduce the risk of an adverse effect for the population as a whole. Individual hypersensitivity (sometimes referred to as intolerance) cannot be predicted currently but appears to be relatively uncommon.
The quality and scope of toxicity studies has improved enormously in the last few decades, and has been invaluable in maintaining standards for public health.
Are toxicological reports available to the public?
Yes. Public Release Summary documents on new agricultural and veterinary chemicals, and full assessment reports of old pesticides which have undergone review are available from the APVMA. Assessment reports on industrial chemicals which have been reviewed (so-called Priority Existing Chemicals or PECs) are available from NICNAS.
Further information
Information and advice on chemical safety in relation to public health may be obtained by contacting:
Office of Chemical Safety
Therapeutic Goods Administration
Australian Government Department of Health and Ageing
[Mail Drop Point 88]
PO Box 100
Woden ACT 2606
Telephone 02 6289 3200
Website: http://www.ocs.gov.au
Information on food standards may be obtained by contacting:
Food Standards Australia New Zealand
PO Box 7186
Canberra Mail Centre ACT 2610
Telephone 02 6271 2222
FSANZ website: http://www.foodstandards.gov.au
Information on industrial chemicals may be obtained by contacting:
National Industrial Chemicals Notification and Assessment Scheme
GPO Box 58
Sydney NSW 2001
Telephone 02 9577 9578
NICNAS website: http://www.nicnas.gov.au
Information on registration of agricultural and veterinary chemicals may be obtained by contacting:
Australian Pesticides and Veterinary Medicines Authority
PO Box E240
Kingston ACT 2604
Telephone: 02 6272 5158
NRA website: http://www.apvma.gov.au