Transcript Toxicant
Chapter 2 –Toxicology Definitions, Entry to Biological organism and elimination, Effects of toxicants on biological organisms, Dose versus response, Models for dose and response curves, Threshold limit values Definitions Toxicology: - entry of toxicants into organism •elimination from organism •effects on organism Toxicology is the qualitative and quantitative study of the adverse effects of toxicants on biological organisms Industrial hygiene: prevention or reduction of entry (Chapter 3) Toxicant • chemical agents • physical agents: particulates < 5 μm, noise, radiation Toxicity: property related to effect on organism Problem: organisms respond via a distribution of effects Toxic hazard: likelihood of damage to biological organisms based on exposure “All substances are poisons; there is none which is not poison. The right dose differentiates a poison and a remedy” (Paracelsus, 1500s) How Toxicants Enter Biological Organisms? Toxicant enters the organisms → moves into the bloodstream → elimination or organ transportation to target Table 2.1: Entry Routes for Toxicants and Methods for control Entry Route Entry Organ Method for Control Ingestion Mouth or stomach Enforcement of rules on eating, drinking and smoking Inhalation Mouth or nose Ventilation, respirators, hoods and other personal protection equipment Injection Cuts in skin Proper protective clothing Dermal absorption Skin Proper protective clothing Source: Crowl and Louvar (2002) Toxic blood levels Routes and elimination Toxicological Studies Objective: To quantify the effects of the suspect toxicants on target organism. Biological organisms respond differently to the same dose of a toxicant as a result of age, sex, weight, general health and other factors. The following items must be identified: • Toxicant: chemical composition and physical state. Example: Benzene (vap or liq ??) different routs of entry • Target or test organism: from single cell to higher animal. (cost and availability) • Dose unit. ( milligrams of agent per kilogram of body weight) • Period of the test. Acute toxicity is the effect of a single exposure or a series of exposures close together in a short period of time. Chronic toxicity is the effect of multiple exposures occurring over a long period of time. Chronic toxicity studies are difficult to perform because of the time involved; most toxicological studies are based on acute exposures Tests are carried out on animals such as mice and rabbits. very poor animal indeed! Dose versus Response Now, it’s the time to refresh our skills in statistics! Gaussian chart plot or Normal distribution µ is the arithmetic mean n x f (x ) i 1 n i i f (x ) i 1 i f ( x ) = probability (or fraction) of individuals experiencing a specific response x = response σ = the standard deviation 1 21( x )2 f ( x) e 2 •Standard deviation measures how the data are spread out with respect to the mean Standard deviation •The bigger σ, the more spread the data are •Area under the curve represents the percentage of individuals affected for a specific response interval Example 2.1 Seventy-five people are tested for skin irritation of a specific dose of a substance. The responses are recorded on a scale from 0 to 10, with 0 indicating no response and 10 indicating a high response. The number of individuals exhibiting a specific response is given in the following table : i.Plot a histogram of the number of individuals affected versus the response. ii.Determine the mean and the standard Deviation. iii.Plot the normal distribution curve on the histogram of the original data. Solution: σ = 2.24 Dose versus Response When you injected 100 rabbits with a substance, you will find that they respond differently. Some of them will suffer even at small dose, while other need bigger doses to feel the same pain!. Dose Response category D1 (for example 1ppm) 1 (to denote for example “not being felt”) D2 2 D3 3 to denote for example (“severe impact’) D4 (for example 100 ppm) 4 (to denote for example “death”) Convert this table to figure This plot is not very useful, especially at low doses. So we produce the log curve which takes the S-shape Dose versus Response • • • • Dose → 50% lethality (LD50) used for comparison. (LD10 and LD90) sometimes also used. For gases → LC (Lethal Concentration) curve For minor and reversible responses → ED (Effective Dose) curve Toxics (not lethal, but irreversible response) → TD (Toxic Dose) curve Models for Dose and Response Curves •Response vs. dose curves can be drawn for a wide variety of exposures, including exposure to heat, pressure, radiation, impact, and sound. For computational purposes such curve is not convenient; an analytical equation is preferred •Change S-shape into straight line using a mathematical transformation called a probit. (probit= probability unit) •In mathematical terms probit is a straight line probability relationship developed to measure, for example, killing a certain proportion of the population, expressed as a standard deviation and related to a mean of 5. It has the advantage of being easily used without deep understanding of the underlying theory, provided suitable data is available. •Using probits, most response vs. dose curves can be represented in the form: Y = k1+ k2 ln ( V ) where Y = Probit variable k1, k2 are constants V = causative variable (the magnitude of the exposure such as heat, pressure, radiation, impact, and sound in their rightfull units) Models for Dose and Response Curves Probit (probability unit) Method provides straight-line equivalent to response-dose curve 1 P (2 )1/ 2 Y 5 u2 exp 2 du more pratical to use Y 5 Y 5 P 50 1 erf Y 5 2 Y k1 k 2 ln V Transformations from Percentages to Probit Relative Toxicity Toxicity might differ with the amount of dose Two toxicants with differing relative toxicities at different doses. Toxicant A is more toxic at high doses, whereas toxicant B is more toxic at low doses. Threshold Limit Values Threshold dose: The lowest value in the response vs. dose curve below which the body is able to detoxify the agent without any detectable effects Threshold Limit Value - TLV: airborne concentrations that correspond to conditions under which no adverse effects are normally expected during worker’s life time Often called maximum allowable concentration (MAC) TLV values are Published by ACGIH: American Conference of Governmental Industrial Hygienists (ACGIH), a professional organization without legal authority Some materials have zero threshold IDLH: Immediately Dangerous to Life and cause Death , thus Exposure should be avoided. Values in Table are tabulated. For vapors, mg/m3 is converted to ppm using the equation Examples for TLV TLVs are reported using ppm (parts per million by volume), mg/m3 (milligrams of vapor per cubic meter of air), or, for dusts, mg/m3 or mppcf (millions of particles per cubic foot of air). PEL - Permissible Exposure Level (another system) versus TLV •Published by OSHA, and have legal authority. •Defined in the same way as TLV. •Most PELs are same as TLVs. •Not updated as regularly as TLVs. •Most companies use lowest of the two values . •TLV estimates assume that workers are only exposed during the normal eight-hour workday. •Companies use the lowest values of both. In all cases, every effort must be done to reduce worker exposures to toxicants to below the PEL and lower if possible.