Exposure standards and guidelines
Exposure standards and guidelines are developed by governments to protect the public from harmful substances and activities that can cause serious health problems. Only standards and guidelines relating to protection from the toxic effects of chemicals follow.
Exposure standards and guidelines are the products of risk management decisions. Risk assessments provide regulatory agencies with estimates of numbers of persons potentially harmed under specific exposure conditions. Regulatory agencies then propose exposure standards and guidelines which will protect the public from unacceptable risk.
Exposure standards and guidelines usually provide numerical exposure levels for various media (such as food, consumer products, water and air) that cannot be exceeded. Alternatively, these standards may be preventive measures to reduce exposure (such as labeling, special ventilation, protective clothing and equipment, and medical monitoring).
Exposure standards and guidelines are of two types:
Federal and state regulatory agencies have the authority to issue permissible exposure standards and guidelines. They include the following categories: Consumer Product Exposure Standards and Guidelines, Environmental Exposure Standards and Guidelines, and Occupational Exposure Standards and Guidelines.
Consumer Product Exposure Standards and Guidelines
Manufacturers of new pharmaceuticals are required to obtain formal FDA approval before their products can be marketed. Drugs intended for use in humans must be tested in humans (in addition to animals) to determine toxic dose levels as a part of the new drug application (NDA).
The NDA covers all aspects of a drug's effectiveness and safety, including:
- pharmacokinetics and pharmacological effects
- metabolism and mechanism of action
- associated risks of the drug
- intended uses and their effectiveness
- benefit-risk relationship
- basis for package inserts supplied to physicians
The FDA does not issue exposure standards for drugs. Instead, FDA approves an NDA which contains guidance for usage and warnings concerning effects of excessive exposure to the drug. The manufacturer is required to provide this information to physicians prescribing the drug as well as to the others that may purchase or use the drug. Information on a drug's harmful side effects is provided in three main ways:
- labeling and package inserts that accompany a drug and explain approved uses, recommended dosages, and effects of overexposure
- publication of information in the Physicians' Desk Reference (PDR)
- information dissemination to physicians via direct mailing or by publications in medical journals
The package insert labels and the PDR contain information pertaining to the drugs:
- clinical pharmacology
- indications and usage
- adverse reactions
- available forms
- dosage and administration
The FDA is responsible for the approval of food additives. Standards are different depending on whether they are direct food additives or indirect food additives. Direct food additives are intentionally added to foods for functional purposes. Examples of direct food additives are processing aids, texturing agents, preservatives, flavoring and appearance agents, and nutritional supplements. Approval usually designates the maximum allowable concentrations (e.g., 0.05%) in a food product.
Indirect food additives are not intentionally added to foods and they are not natural constituents of foods. They become a constituent of the food product from environmental contamination during production, processing, packaging and storage. Examples of indirect food additives are antibiotics administered to cattle, pesticide residues remaining after production or processing of foods, and chemicals that migrate from packaging materials into foods. Exposure standards indicate the maximum allowable concentration of these substances in food.
New direct food additives must undergo stringent review by FDA scientists before they can be approved for use in foods. The manufacturer of a direct food additive must provide evidence of the safety of the food additive in accordance with specified uses. The safety evaluation is conducted by the toxicity testing and risk assessment procedures previously discussed with derivation of the ADI. In contrast to pharmaceutical testing, virtually all toxicity evaluations are conducted with experimental laboratory animals.
In 1958, with an amendment to the Food, Drug and Cosmetic Act (FDCA), FDA was required to approve all new food additives. The law at that time decided that all existing food additives were generally recognized as safe (known as GRAS) and no exposure standard was developed. Many of these GRAS substances have more recently been re-evaluated and maximum acceptable levels have been established.
The FDA re-evaluation of GRAS substances requires that specific toxicity tests be conducted based on the level of the GRAS substance in a food product. For example, the lowest level of concern is for an additive used at 0.05 parts per million (ppm) in the food product. Only short-term tests (a few weeks) are required for those compounds. In contrast, a food additive used at levels higher than 1.0 ppm must be tested for carcinogenicity, chronic toxicity, reproductive toxicity, developmental toxicity, and mutagenicity.
The 1958 amendment to the FDCA law for FDA is known as the Delaney Clause. This clause prohibits the addition of any substance to food that has been shown to induce cancer in man or animals. The implication is that any positive result in an animal test, regardless of dose level or mechanism, is sufficient to prohibit use of the substance. In this case, the allowable exposure level is zero.
Consumer exposure standards are developed for hazardous substances and articles by the Consumer Product and Safety Commission (CPSC). Their authority under the Federal Hazardous Substance Act pertains to substances other than pesticides, drugs, foods, cosmetics, fuels, and radioactive materials. The CPSC requires a warning label on a consumer product which is toxic, corrosive, irritant, or sensitizer. Highly toxic substances are labeled with "DANGER"; less toxic substances are labeled with "WARNING" or "CAUTION".
The basis for "highly toxic" is a median lethal oral dose (or LD50)in laboratory rats of 50 milligrams per kilogram of body weight (mg/kg or ppm) or less, an inhaled dose in rats of 200 ppm for one hour, and a 24-hour dermal dose in rabbits of 200 mg/kg. A substance is corrosive if it causes visible destruction or irreversible damage to the skin or eye. If it causes damage which is reversible within 24 hours, it is designated an irritant. An immune response from a standard sensitization test in animals is sufficient for designation as a sensitizer.
Environmental Exposure Standards and Guidelines
The Environmental Protection Agency (EPA) is responsible for several laws that require determination and enforcement of exposure standards. In addition, they have the authority to prepare recommended exposure guidelines for selected environmental pollutants.
The EPA is responsible for developing exposure standards for:
- water pollutants
- air pollutants
- hazardous wastes
Pesticides can not be marketed until they have been registered by the EPA in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). In order to obtain registration, a pesticide must undergo an extensive battery of toxicity tests, chemistry analyses, and environmental fate tests.
In cases where the toxicity warrants, a pesticide may be approved for restricted uses. A primary exposure standard for pesticides is the pesticide tolerance for food use. This standard specifies the amount of pesticide that is permitted on raw food products (e.g., tolerance for chlorpyrifos on corn).
Water pollutants are regulated by two laws, the Safe Drinking Water Act (SDWA) and the Clean Water Act (CWA). Under the SDWA, the EPA conducts risk assessments and issues maximum contaminant levels (MCLs) for chemicals in drinking water sources including: rivers, lakes, reservoirs, springs, and ground water wells, although the SDWA does not regulate private wells which serve fewer than 25 individuals. The MCL is the acceptable exposure level which, if exceeded, requires immediate water treatment to reduce the contaminant level. For example, the MCL for trichloroethylene is 0.005 mg per liter of water.
In addition to establishing MCLs, the EPA can propose recommended exposure guidance for drinking water contamination. As an interim procedure, maximum contaminant level goals (MCLGs) may be recommended for long-term exposures to contaminants in drinking water. Generally, no allowable exposure can be recommended for a carcinogenic chemical. When the MCL is issued, an acceptable exposure level based on a cancer risk assessment may be proposed for the MCL. For example, the MCLG for chlordane is 0 mg/L whereas the MCL is 0.002 mg/L.
EPA prepares health advisories (HAs) as voluntary exposure guidelines for drinking water contamination. The HAs provide exposure limits for 1-day, 10-day, longer-term, or lifetime exposure periods. They pertain only to non-carcinogenic risks. The formula used to derive a health advisory differs from that for the ADI or reference dose (RfD) in that the HAs pertain to short-term as well as long-term exposures. In addition, human body weight and drinking water consumption are included in the formula. The basic formula for an HA (in mg/L) is:
The durations and exposure route (oral) of the toxicology studies to be employed for HA assessments must conform with the human exposures covered by the HAs. For example, the NOAEL or LOAEL for derivation of a 10-day HA would be obtained from an animal toxicity test of approximately 10 days duration (routinely 7-14 day toxicity studies).
A longer-term HA applies to humans drinking contaminated water for up to 7 years (10% of a human's 70-year lifespan). Since 90 days is about 10% of a rats expected lifespan, the 90-day subchronic study with rats is appropriate for derivation of the longer-term HA assessment.
A life-time HA (representing lifetime exposure to a toxicant in drinking water) is also determined for non-carcinogens. The procedure uses the RfD risk assessment with adjustments for body weight of an adult human (70 kg) and drinking water consumption of 2 L/day.
In addition to drinking water standards, the EPA is authorized under the Clean Water Act (CWA) to issue exposure guidance for control of pollution in surface water. The intent is to provide clean water for fishing and swimming rather than for drinking purposes. It provides a scheme for controlling the introduction of pollutants into navigable surface water. The recommendations for water protection are known as ambient water quality criteria.
The ambient water quality criteria are intended to control pollution sources at the point of release into the environment. While these criteria may be less restrictive than the drinking water standards, they usually are the same numeric value. For example, the MCL (for drinking water) and the ambient water quality criteria (for groundwater) for lead are the same (0.05 mg per liter of water).
Air emission standards are issued by EPA under the Clean Air Act (CAA). The CAA authorizes the issuance of national ambient air quality standards (NAAQS) for air pollution. There are two types of NAAQS. Primary NAAQS pertain to human health, whereas secondary NAAQS pertain to public welfare (such as crops, animals, and structures).
NAAQS have been established for the following major atmospheric pollutants: carbon monoxide, sulfur oxides, oxides of nitrogen, ozone, hydrocarbons, particulates, and lead. When air emissions exceed the NAAQS levels, the polluting industry must take control measures to reduce emissions to the acceptable level.
Hazardous wastes are regulated under the Resource Conservation and Recovery Act (RCRA) and the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), commonly known as Superfund. RCRA regulates hazardous chemical waste produced by industrial processes, medical waste and underground storage tanks.
The main purpose of CERCLA is to clean up hazardous waste disposal sites. EPA has established standards known as Reportable Quantities (RQs). Companies must report to EPA any chemical release that exceeds the RQ. The RQ for most hazardous substances is one pound.
ATSDR derives Minimal Risk Levels (MRLs) for noncancer toxic effects. MRLs are estimates of daily human exposures that are considered to be without an appreciable risk of adverse effects over a specified duration of exposure. MRLs are derived for acute (14 days or less), intermediate (15-364 days), and chronic (365 days or more) exposures for inhalation or oral routes.
Occupational Exposure Standards and Guidelines
Legal standards for workplace exposures are established by the Occupational Safety & Health Administration (OSHA). These standards are known as Permissible Exposure Limits (PELs). Most OSHA PELs are for airborne substances with allowable exposure limits averaged over an 8-hour day, 40-hour week. This is known as the Time-Weighted-Average (TWA) PEL. Adverse effects should not be encountered with repeated exposures at the TWA PEL.
OSHA also issues Short Term Exposure Limit (STELs) PELs, Ceiling Limit PELs, and PELs that carry a skin designation. PEL STELs are concentration limits of substances in the air that a worker may be exposed to for 15 minutes without suffering adverse effects. The 15 minute STEL is usually considerably higher than the 8-hour TWA exposure level. For example, for trichloroethylene the PEL-STEL is 200 ppm whereas the PEL-TWA is 50 ppm.
Ceiling Limit PELs are concentration limits for airborne substances that should never be exceeded. A skin designation indicates that the substance can be readily absorbed through the skin, eye or mucous membranes, and substantially contribute to the dose that a worker receives from inhalation of the substance.
Theoretically, an occupational substance could have PELs as TWA, STEL, and Ceiling Limit, and with a skin designation. This is rare however. Usually, an OSHA regulated substance will have only a PEL as a time-weighted average. About 20% of the OSHA-regulated substances have PEL-STELs and only about 10% have skin notations. In a few cases, a substance may have a PEL-Ceiling but not a PEL-TWA.
An occupational exposure guideline developed by the OSHA Standards Completion Program is the Immediately Dangerous to Life and Health (IDLH). This represents a maximum level that a human could be exposed to for up to 30 minutes and escape from without any serious health effects.
When OSHA was formed in 1971, it immediately adopted existing occupational heath guidelines for its PELs. These guidelines were those of the American National Standards Institute (ANSI), American Conference of Governmental Industrial Hygienists (ACGIH), and National Institute for Occupational Safety and Health (NIOSH). OSHA also developed health standards for over 30 other workplace hazards based on risk assessments that they conducted.
The guidelines issued by the ACGIH are known as Threshold Limit Values (TLVs). NIOSH guidelines are designated as NIOSH Recommended Exposure Limits (RELs). Three types of TLVs exist as previously described for OSHA PELs. They are: Threshold Limit Value Time-Weighted Average (TLV-TWA), TLV as a Short-Term Exposure Limit (TLV-STELs), and Threshold Limit Value as a Ceiling Limit (TLV-C). The NIOSH RELs are also designated as time-weighted average, short-term exposure limits and ceiling limits.
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