Toxicology quizzzzz

hazard

Capability of a substance to cause an adverse affect

Risk

Probobility that the hazard will occur under specific exposure conditions

Physical environment and potentially affected population (exposure assessment)

1.The physical environment may include considerations of climate, vegetation, soil type, ground-water and surface water. ● Populations that may be exposed as the result of chemicals that migrate from the site of pollution are also considered. Subpopulations may be at greater risk due to a higher level of exposure or because they have increased sensitivity (infants, elderly, pregnant women, and those with chronic illness).

Uncertainty factor

Any toxic effect might be used for the NOAEL/LOAEL so long as it is the most sensitive toxic effect and considered likely to occur in humans.The Uncertainty Factors (UF) or Safety Factors used to derive an ADI or RfD are: The modifying factor is used only in deriving EPA Reference Doses. The number of factors included in calculating the ADI or RfD depend upon the study used to provide the appropriate NOAEL or LOAEL.The general formula for deriving the RfD is: The more uncertain or unreliable the data becomes, the higher will be the total uncertainty factor that is applied. An example of an RfD calculation is provided below. A subchronic animal study with a LOAEL of 50 mg/kg/day was used. Thus the uncertainty factors are: 10 for human variability, 10 for an animal study, 10 for less than chronic exposure, and 10 for use of an LOAEL instead of a NOAEL.

Cancer Risk assessment

Cancer risk assessment involves two steps. The first step is a qualitative evaluation of all epidemiology studies, animal bioassay data, and biological activity (e.g., mutagenicity). The substance is classified as to carcinogenic risk to humans based on the weight of evidence. If the evidence is sufficient, the substance may be classified as a •definite, •probable or •possible human carcinogen. The second step is to quantitate the risk for those substances classified as definite or probable human carcinogens. Mathematical models are used to extrapolate from the high experimental doses to the lower environmental doses. The two primary cancer classification schemes are those of the Environmental Protection Agency (EPA) and the International Agency for Research on Cancer (IARC). The EPA and IARC classification systems are quite similar. The EPA's cancer assessment procedures have been used by several Federal and State agencies. The Agency for Toxic Substances and Disease Registry (ATSDR) relies on EPA's carcinogen assessments. A substance is assigned to one of six categories as shown at right: The basis for sufficient human evidence is an epidemiology study that clearly demonstrates a causal relationship between exposure to the substance and cancer in humans. The data are determined to be limited evidence in humans if there are alternative explanations for the observed effect. The data are considered to be inadequate evidence in humans if no satisfactory epidemiology studies exist.An increase in cancer in more than one species or strain of laboratory animals or in more than one experiment is considered sufficient evidence in animals. Data from a single experiment can also be considered sufficient animal evidence if there is a high incidence or unusual type of tumor induced. Normally, however, a carcinogenic response in only one species, strain, or study, is considered as only limited evidence in animals.When an agent is classified as a Definite Human or Probable Human Carcinogen, it is then subjected to a quantitative risk assessment. For those designated as a Possible Human Carcinogen, the risk assessor can determine on a case-by-case basis whether a quantitative risk assessment is warranted. The key risk assessment parameter derived from the EPA carcinogen risk assessment is the cancer slope factor. This is a toxicity value that quantitatively defines the relationship between dose and response. The cancer slope factor is a plausible upper-bound estimate of the probability that an individual will develop cancer if exposed to a chemical for a lifetime of 70 years. The cancer slope factor is expressed as mg/kg/day.Mathematical models are used to extrapolate from animal bioassay or epidemiology data to predict low dose risk. Most assume linearity with a zero threshold dose. Exception: endocrine receptors EPA uses the Linearized Multistage Model (LMS) illustrated above to conduct its cancer risk assessments. It yields a cancer slope factor, known as the q1* (pronounced Q1-star) which can be used to predict cancer risk at a specific dose. It assumes linear extrapolation with a zero dose threshold from the upper confidence level of the lowest dose that produced cancer in an animal test or in a human epidemiology study. Example: estimated drinking water concentrations for chlordane that will cause a lifetime risk (probability) of one cancer death in a million persons, derived from different cancer risk assessment models, vary as illustrated below: PB-PK models are relatively new and are being employed when biological data are available. They quantitate the absorption of a foreign substance, its distribution, metabolism, tissue compartments, and elimination. Some compartments store the chemical (bone and adipose tissue) whereas others biotransform or eliminate it (liver or kidney). All these biological parameters are used to derive the target dose and comparable human doses.

Exposure assessment

Exposure assessment is a key phase in the risk assessment process since without an exposure, even the most toxic chemical does not present a threat. All potential exposure pathways are carefully considered. Contaminant releases, their movement and fate in the environment, and the exposed populations are analyzed.

risk assessment

For many years the terminology and methods used in human risk or hazard assessment were not consistent. This led to confusion among scientists and the public. In 1983, the National Academy of Sciences (NAS) published standard terminology and concepts for risk assessments.

Occupational exposures

For occupational exposures, Permissible Exposure Levels (PELs), Threshold Limit Values (TLVs), and NIOSH Recommended Exposure Levels (RELs) are developed. They represent dose levels that will not produce adverse health effects from repeated daily exposures in the workplace. The method used to derive is conceptually the same. Safety factors are used to derive the PELs, TLVs, and RELs. Animal doses must be converted to human dose equivalents. The human dose equivalent is based on the assumption that different species are equally sensitive to the effects of a substance per unit of body weight or body surface area.

Terms used in risk assessment

Hazard risk risk assessment Risk management

Four basic steps in the risk assessment process

Hazard identification- Characterization of innate adverse toxic effects of an agent Dose response assessment- Characterization of the relation between doses and incidences of adverse effects in exposed populations exposure assessment- Measurement or estimation of the intensity, frequency, and duration to human exposures to agents Risk characterization- Estimation of the incidents of health effects under the various conditions of human exposure.

how do FDA and EPA calculate dose equivalents

Historically, FDA used a ratio of body weights of humans to animals to calculate the human dose equivalent. EPA has used a ratio of surface areas of humans to animals to calculate the human dose equivalent. The animal dose was multiplied by the ratio of human to animal body weight raised to the 2/3rd power (to convert from body weight to surface area). FDA and EPA have agreed to use body weight raised to the 3/4th power to calculate human dose equivalents in the future.

Non carcinogenic risk assessment

Historically, the Acceptable Daily Intake (ADI) procedure has been used to calculate permissible chronic exposure levels for humans based on non-carcinogenic effects. The ADI is the amount of a chemical to which a person can be exposed each day for a long time (usually lifetime) without suffering harmful effects. It is determined by applying safety factors (to account for the uncertainty in the data) to the highest dose in human or animal studies which has been demonstrated not to cause toxicity (NOAEL - no observable adverse effect level).The EPA has slightly modified the ADI approach and calculates a Reference Dose (RfD) as the acceptable safety level for chronic non-carcinogenic and developmental effects. Similarly the ATSDR calculates Minimal Risk Levels (MRLs) for non-cancer end points.

Minimal risk levels

In addition to chronic effects, RfDs can also be derived for other long term toxic effects, including developmental toxicity.While ATSDR does not conduct cancer risk assessments, it does derive Minimal Risk Levels (MRLs) for noncancer toxicity effects (such as birth defects or liver damage). The MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects over a specified duration of exposure. For inhalation or oral routes, MRLs are derived for acute (14 days or less), intermediate (15-364 days), and chronic (365 days or more) durations of exposures.The method used to derive MRLs is a modification of the EPA's RfD methodology. The primary modification is that the uncertainty factors of 10 may be lower, either 1 or 3, based on scientific judgment. These uncertainty factors are applied for human variability, interspecies variability (extrapolation from animals to humans), and use of a LOAEL instead of NOAEL. As in the case of RfDs, the product of uncertainty factors multiplied together is divided into the NOAEL or LOAEL to derive the MRL.

exposure to several chemicals

In some complex risk assessments such as for hazardous waste sites, the risk characterization must consider multiple chemical exposures and multiple exposure pathways. Simultaneous exposures to several chemicals, each at a sub-threshold level, can often cause adverse effects by simple summation of injuries. The assumption of dose additivity is most acceptable when substances induce the same toxic effect by the same mechanism. When available, information on mechanisms of action and chemical interactions are considered and are useful in deriving more scientific risk assessments.Individuals are often exposed to substances by more than one exposure pathway (e.g. drinking of contaminated water, inhaling contaminated dust). In such situations, the total exposure will usually equal the sum of the exposures by all pathways.

Hazard identification

In this initial step, the potential for a xenobiotic to induce any type of toxic hazard is evaluated. Information is gathered and analyzed in a weight-of-evidence approach. The types of data usually consist of: •human epidemiology data • •animal bioassay data • •supporting data Based on these results, one or more toxic hazards may be identified (such as cancer, birth defects, chronic toxicity, neurotoxicity). The primary hazard of concern is one in which there is a serious health consequence (such as cancer) that can occur at lower dosages than other serious toxic effects. The primary hazard of concern will be chosen for the dose-response assessment Human epidemiology data are the most desirable and are given highest priority since they avoid the concern for species differences in the toxic response. Unfortunately, reliable epidemiology studies are rarely available. Even when epidemiology studies have been conducted, they usually have incomplete and unreliable exposure histories. For this reason, it is rare that risk assessors can construct a reliable dose-response relationship for toxic effects based on epidemiology studies. More often, the human studies can only provide qualitative evidence that a causal relationship exists. In practice, animal bioassay data are generally the primary data used in risk assessments. Animal studies are well-controlled experiments with known exposures and employ detailed, careful clinical, and pathological examinations. The use of laboratory animals to determine potential toxic effects in humans is a necessary and accepted procedure. It is a recognized fact that effects in laboratory animals are usually similar to those observed in humans at comparable dose levels. Exceptions are primarily attributable to differences in the toxico-(pharmaco-)kinetics and metabolism of the xenobiotics. Supporting data derived from cell and biochemical studies may help the risk assessor make meaningful predictions as to likely human response. For example, often a chemical is tested with both human and animal cells to study its ability to produce cytotoxicity, mutations, and DNA damage. The cell studies can help identify the mechanism by which a substance has produced an effect in the animal bioassay. In addition, species differences may be revealed and taken into account.A chemical's toxicity may be predicted based on its similarity in structure to that of chemical for which the toxicity is known. This is known as a structure-activity relationship (SAR). The SAR has only limited value in risk assessment due to exceptions to the predicted toxicity.

Potential human carcinogenic risks

Potential human carcinogenic risks associated with chemical exposure are expressed in terms of an increased probability of developing cancer during a person's lifetime. For example, a 10-6 increased cancer risk represents an increased lifetime risk of 1 in 1,000,000 for developing cancer. For carcinogenicity, the probability of an individual developing cancer over a lifetime is estimated by multiplying the cancer slope factor (mg/kg/day) for the substance by the chronic (70-year average) daily intake (mg/kg-day). For non-carcinogenic effects, the exposure level is compared with an ADI, RfD or MRL derived for similar exposure periods. Three exposure durations are considered: acute, intermediate, or chronic. For humans, acute effects are considered those that arise within days to a few weeks, intermediate effects are those evident in weeks to a year, and chronic effects are those that become manifest in a year or more.

Health advisories (HA's)

Risk assessments are also conducted to derive permissible exposure levels for acute or short term exposures to chemicals. Health Advisories (HAs) are determined for chemicals in drinking water. HAs are the allowable human exposures for one day, ten days, longer-term, and lifetime durations. The method used to calculate HAs is similar to that for the RfD's using uncertainty factors. Data from toxicity studies with durations of length appropriate to the HA are being developed.

Risk assessment process

Risk assessments may be conducted for individual chemicals or for complex mixtures of chemicals. In cases of complex mixtures, such as hazardous waste sites, the process of risk assessment itself becomes quite complex. This complexity results from: •simultaneous exposure to many substances with the potential for numerous chemical and biological interactions •exposures by multiple media and pathways (e.g., via water, air, and soil) •exposure to a wide array of organisms with differing susceptibilities (e.g., infants, adults, humans, animals, environmental organisms) Conducting scientifically sound risk assessments is of great national importance. An error in undercalculating risk probabilities could lead to overexposure of the population. On the other hand, an overcalculation of risk could result in unwarranted costs to the public. As illustrated below, the cost to clean-up a hazardous waste site varies greatly with the degree of clean-up required which is determined by risk assessments.

Risk management definition

Risk management decisions follow the identification and quantification of risk which are determined by risk assessments. During the regulatory process, risk managers may request that additional risk assessments be conducted to justify the risk management decisions. As indicated in the figure above, the risk assessment and risk management processes are intimately related.

The critical toxic effect

The critical toxic effect used in the calculation of an ADI, RfD, or MRL is the serious adverse effect which occurs at the lowest exposure level. It may range from lethality to minor toxic effects. It is assumed that humans are as sensitive as the animal species unless evidence indicates otherwise.In determining the ADIs, RfDs or MRLs, the NOAEL is divided by safety factors (uncertainty factors) in order to provide a margin of safety for allowable human exposure

dose-response assessment

The dose-response assessment step quantitates the hazards which were identified in the hazard evaluation phase. It determines the relationship between dose and incidence of effects in humans. There are normally two major extrapolations required. •The first is from high experimental doses to low environmental doses and •the second from animal to human doses. The procedures used to extrapolate from high to low doses are different for assessment of carcinogenic effects and non-carcinogenic effects. Carcinogenic effects are not considered to have a threshold and mathematical models are generally used to provide estimates of carcinogenic risk at very low dose levels.Noncarcinogenic effects (e.g. neurotoxicity) are considered to have dose thresholds below which the effect does not occur. The lowest dose with an effect in animal or human studies is divided by Safety Factors to provide a margin of safety.

Last step in dose response

The last step in dose-response assessment is to express the risk in terms of allowable exposure to a contaminated source. Risk is expressed in terms of the concentration of the substance in the environment where human contact occurs. For example, the unit risk in air is risk per mg/m3 whereas the unit risk in drinking water is risk per mg/L.For carcinogens, the media risk estimates are calculated by dividing cancer slope factors by 70 kg (average weight of man) and multiplying by 20 m3/day (average inhalation rate of an adult) or 2 liters/day (average water consumption rate of an adult).

Risk assessment

The process by which hazard, risk ,and exposure are determined

Risk management

The process of weighing policy alternatives and selecting the most appropriate regulatory action based on the results of risk assessment and social, economic, and political concerns

Final stage in risk assessment

This final stage in the risk assessment process involves prediction of the frequency and severity of effects in exposed populations. Conclusions reached concerning hazard identification and exposure assessment are integrated to yield probabilities of effects likely to occur in humans exposed under similar conditions.Since most risk assessments include major uncertainties, it is important that biological and statistical uncertainties are described in the risk characterization. The assessment should identify which components of the risk assessment process involve the greatest degree of uncertainty.

NOAEL and LOAEL

When a NOAEL is not available, a LOAEL can be used to calculate the RfD. An additional safety factor is included if a LOAEL is used. A Modifying Factor of 0.1-10 allows risk assessors to use scientific judgment in upgrading or downgrading the total uncertainty factor based on the reliability and quality of the data. For example, if a particularly good study is the basis for the risk assessment, a modifying factor of < 1 may be used. If a poor study is used, a factor of >1 can be incorporated to compensate for the uncertainty associated with the quality of the study.

exposure assessment includes 3 steps

•characterization of the exposure setting (e.g., point source) •identification of exposure pathways (e.g., groundwater) •quantification of the exposure (e.g., µg/L water)

The main variables in the exposure assessment are:

•exposed populations (general public or selected groups) •types of substances (pharmaceuticals, occupational chemicals, or environmental pollutants) •single substance or mixture of substances •duration of exposure (brief, intermittent, or protracted) •pathways and media (ingestion, inhalation, and dermal exposure)

Pollutants may be transported away from the source. They may be physically, chemically or biologically transformed. They may also accumulate in various media. Assessment of the chemical fate requires knowledge of many factors including:

•organic carbon and water partitioning at equilibrium (Koc) •chemical partitioning between soil and water (Kd) •partitioning between air and water (Henry's Law Constant) •solubility constants •vapor pressures •partitioning between water and octanol (Kow) •bioconcentration factors (BCF) These factors are integrated with the data on sources, releases and routes of the pollutants to determine the exposure pathways of importance. Exposure pathways may include: •groundwater •surface water •air •soil •food breast-milk