Exposure, Dose, and Response Study Guide PDF

FM-AA-CIA-15 Rev. 0 10-July-2020 Study Guide in ESM 4: Air Quality and Environmental Toxicology Module No. ESM- 07 STUDY GUIDE FOR MODULE NO. ESM 4- 7 Exposure, Dose, and Response...

FM-AA-CIA-15 Rev. 0 10-July-2020 Study Guide in ESM 4: Air Quality and Environmental Toxicology Module No. ESM- 07 STUDY GUIDE FOR MODULE NO. ESM 4- 7 Exposure, Dose, and Response MODULE OVERVIEW This is the third Module on ESM4: Air Quality and Environmental Toxicology. This course consists of two lecture hours and three laboratory hours per week. This Module ESM 4-07 describes exposure, dose, and response. MODULE LEARNING OBJECTIVES At the end of this Module ESM 4-07, the students should be able to discuss 1. dose 2. response 3 threshold dose LEARNING CONTENTS General Instructions: 1. Please read the Module diligently. 2. If you have questions and suggestions, please write them specifically and send it to the Instructor’s email: [email protected] 3. Do not post any part of this Module on social media. 4. Please check references for more information. If there are additional information and updated data, please write the reference (Author, Date of Publication and Web Link, if available.) Exposure, Dose and Response Toxicity is the intrinsic capacity of a chemical agent to affect an organism adversely. Xenobiotics is a term for “foreign substances”, that is, foreign to the organism. Its opposite is endogenous compounds. Xenobiotics include drugs, industrial chemicals, naturally occurring poisons and environmental pollutants. Hazard is the potential for the toxicity to be realized in a specific setting or situation. Risk is the probability of a specific adverse effect to occur. It is often expressed as the percentage of cases in a given population and during a specific time period. A risk estimate can be based upon actual cases or a projection of future cases, based upon extrapolations. Toxicity rating and toxicity classification can be used for regulatory purposes. Toxicity rating is an arbitrary grading of doses or exposure levels causing toxic effects. The grading can be “supertoxic,” “highly toxic,” “moderately toxic” and so on. The most common ratings concern acute toxicity. Toxicity classification concerns the grouping of chemicals into general categories according to their most important toxic effect. Such categories can include allergenic, neurotoxic, carcinogenic and so on. This classification can be of administrative value as a warning and as information. The dose-effect relationship is the relationship between dose and effect on the individual level. An increase in dose may increase the intensity of an effect, or a more severe effect may result. A dose-effect curve may be obtained at the level of the whole organism, the cell or the target molecule. Some toxic effects, such as death or cancer, are not graded but are “all or none” effects. PANGASINAN STATE UNIVERSITY 1  FM-AA-CIA-15 Rev. 0 10-July-2020 Study Guide in ESM 4: Air Quality and Environmental Toxicology Module No. ESM- 07 The dose-response relationship is the relationship between dose and the percentage of individuals showing a specific effect. With increasing dose a greater number of individuals in the exposed population will usually be affected. It is essential to toxicology to establish dose-effect and dose-response relationships. In medical (epidemiological) studies a criterion often used for accepting a causal relationship between an agent and a disease is that effect or response is proportional to dose. Several dose-response curves can be drawn for a chemical—one for each type of effect. The dose-response curve for most toxic effects (when studied in large populations) has a sigmoid shape. There is usually a low-dose range where there is no response detected; as dose increases, the response follows an ascending curve that will usually reach a plateau at a 100% response. The dose-response curve reflects the variations among individuals in a population. The slope of the curve varies from chemical to chemical and between different types of effects. For some chemicals with specific effects (carcinogens, initiators, mutagens) the dose-response curve might be linear from dose zero within a certain dose range. This means that no threshold exists and that even small doses represent a risk. Above that dose range, the risk may increase at greater than a linear rate. Variation in exposure during the day and the total length of exposure during one’s lifetime may be as important for the outcome (response) as mean or average or even integrated dose level. High peak exposures may be more harmful than a more even exposure level. This is the case for some organic solvents. On the other hand, for some carcinogens, it has been experimentally shown that the fractionation of a single dose into several exposures with the same total dose may be more effective in producing tumours. A dose is often expressed as the amount of a xenobiotic entering an organism (in units such as mg/kg body weight). The dose may be expressed in different (more or less informative) ways: exposure dose, which is the air concentration of pollutant inhaled during a certain time period (in work hygiene usually eight hours), or the retained or absorbed dose (in industrial hygiene also called the body burden), which is the amount present in the body at a certain time during or after exposure. The tissue dose is the amount of substance in a specific tissue and the target dose is the amount of substance (usually a metabolite) bound to the critical molecule. The target dose can be expressed as mg chemical bound per mg of a specific macromolecule in the tissue. To apply this concept, information on the mechanism of toxic action on the molecular level is needed. The target dose is more exactly associated with the toxic effect. The exposure dose or body burden may be more easily available, but these are less precisely related to the effect. In the dose concept a time aspect is often included, even if it is not always expressed. The theoretical dose according to Haber’s law is D = ct, where D is dose, c is concentration of the xenobiotic in the air and t the duration of exposure to the chemical. If this concept is used at the target organ or molecular level, the amount per mg tissue or molecule over a certain time may be used. The time aspect is usually more important for understanding repeated exposures and chronic effects than for single exposures and acute effects. Additive effects occur as a result of exposure to a combination of chemicals, where the individual toxicities are simply added to each other (1+1=2). When chemicals act via the same mechanism, additivity of their effects is assumed although not always the case in reality. Interaction between chemicals may result in an inhibition (antagonism), with a smaller effect than that expected from addition of the effects of the individual chemicals (1+12). Latency time is the time between first exposure and the appearance of a detectable effect or response. The term is often used for carcinogenic effects, where tumours may appear a long time after the start of exposure and sometimes long after the cessation of exposure. A dose threshold is a dose level below which no observable effect occurs. Thresholds are thought to exist for certain effects, like acute toxic effects; but not for others, like carcinogenic effects (by DNA-adduct-forming initiators). The mere absence of a response in a given population should not, however, be taken as evidence for the existence of a threshold. Absence of response could be due to simple statistical phenomena: an adverse effect occurring at low frequency may not be detectable in a small population. PANGASINAN STATE UNIVERSITY 2  FM-AA-CIA-15 Rev. 0 10-July-2020 Study Guide in ESM 4: Air Quality and Environmental Toxicology Module No. ESM- 07 LD50 (effective dose) is the dose causing 50% lethality in an animal population. The LD50 is often given in older literature as a measure of acute toxicity of chemicals. The higher the LD 50, the lower is the acute toxicity. A highly toxic chemical (with a low LD50) is said to be potent. There is no necessary correlation between acute and chronic toxicity. ED50 (effective dose) is the dose causing a specific effect other than lethality in 50% of the animals. NOEL (NOAEL) means the no observed (adverse) effect level, or the highest dose that does not cause a toxic effect. To establish a NOEL requires multiple doses, a large population and additional information to make sure that absence of a response is not merely a statistical phenomenon. LOEL is the lowest observed effective dose on a dose-response curve, or the lowest dose that causes an effect. A safety factor is a formal, arbitrary number with which one divides the NOEL or LOEL derived from animal experiments to obtain a tentative permissible dose for humans. This is often used in the area of food toxicology, but may be used also in occupational toxicology. A safety factor may also be used for extrapolation of data from small populations to larger populations. Safety factors range from 100 to 103. A safety factor of two may typically be sufficient to protect from a less serious effect (such as irritation) and a factor as large as 1,000 may be used for very serious effects (such as cancer). The term safety factor could be better replaced by the term protection factor or, even, uncertainty factor. The use of the latter term reflects scientific uncertainties, such as whether exact dose-response data can be translated from animals to humans for the particular chemical, toxic effect or exposure situation. Extrapolations are theoretical qualitative or quantitative estimates of toxicity (risk extrapolations) derived from translation of data from one species to another or from one set of dose-response data (typically in the high dose range) to regions of dose-response where no data exist. Extrapolations usually must be made to predict toxic responses outside the observation range. Mathematical modelling is used for extrapolations based upon an understanding of the behaviour of the chemical in the organism (toxicokinetic modelling) or based upon the understanding of statistical probabilities that specific biological events will occur (biologically or mechanistically based models). Some national agencies have developed sophisticated extrapolation models as a formalized method to predict risks for regulatory purposes. (See discussion of risk assessment later in the chapter.) Systemic effects are toxic effects in tissues distant from the route of absorption. Target organ is the primary or most sensitive organ affected after exposure. The same chemical entering the body by different routes of exposure dose, dose rate, sex and species may affect different target organs. Interaction between chemicals, or between chemicals and other factors may affect different target organs as well. Acute effects occur after limited exposure and shortly (hours, days) after exposure and may be reversible or irreversible. Chronic effects occur after prolonged exposure (months, years, decades) and/or persist after exposure has ceased. Acute exposure is an exposure of short duration, while chronic exposure is long-term (sometimes life-long) exposure. Tolerance to a chemical may occur when repeat exposures result in a lower response than what would have been expected without pretreatment. LEARNING ACTIVITY Review the module. Read the questions and instructions carefully. Submit your answers on or before next meeting. Activity 7: Give examples of exposure, dose, and response SUMMARY Variation in exposure during the day and the total length of exposure during one’s lifetime may be as important for the outcome (response) as mean or average or even integrated dose level. High peak exposures may be more harmful than a PANGASINAN STATE UNIVERSITY 3  FM-AA-CIA-15 Rev. 0 10-July-2020 Study Guide in ESM 4: Air Quality and Environmental Toxicology Module No. ESM- 07 more even exposure level. A dose is often expressed as the amount of a xenobiotic entering an organism (in units such as mg/kg body weight). In the dose concept a time aspect is often included, even if it is not always expressed. The theoretical dose according to Haber’s law is D = ct, where D is dose, c is concentration of the xenobiotic in the air and t the duration of exposure to the chemical. Latency time is the time between first exposure and the appearance of a detectable effect or response. The term is often used for carcinogenic effects, where tumours may appear a long time after the start of exposure and sometimes long after the cessation of exposure. REFERENCES Library Books Tayo, Gilma T. et.al. 2004. Fundamentals of Environmental Science. 363.7 F96 Cunningham, William P. 2012. Environmental Science: A Global Concern. 363.7 C973e A. Panneerselvam & Mohana Ramakrishnan. 2005. Environmental Sience Education. 301.31 R19e Misra, Rabi N. (ed). 2014. Environment-2025. 363.7 M678r Lee, Sergio J. & Myrna Anez. 2010. Lecture Notes in Environmental Science, 2nd ed. 574.526 L522l Dr. Pawan Kumar Bharti. 2013. Environmental Health and Problems. 620.85En57 e-sources https://www.atsdr.cdc.gov/training/toxmanual/pdf/module-1.pdf https://ec.europa.eu/health/ph_projects/2003/action3/docs/2003_3_09_a21_en.pdf http://ocw.jhsph.edu/courses/publichealthtoxicology/PDFs/Lecture1_Trush.pdf https://www.researchgate.net/publication/308079020_Introduction_to_Toxicology https://toxlearn.nlm.nih.gov/Toxicology/tx010101/tx010101.pdf https://migreenchemistry.org/wp-content/uploads/2013/05/Intrduction-to-Toxicology-Lecture-Slides.pdf PANGASINAN STATE UNIVERSITY 4