Environmental Risk Assessment Toxicity Assessment

Transcription

1 Environmental Risk Assessment Toxicity Assessment UT Evening School Course Spring Semester 2000 Class #07 on February 29, 2000 Environmental Engineering EV595 Martin Clauberg, Ph.D. 1

2 Outline of discussion Toxicity Assessment based on Toxicology ADME Conditions of Exposure Targets of Toxicity Types of Toxicity Mechanisms of Toxicity Interaction of Toxic chemicals in body 2

3 Outline of discussion (cont( cont.) Derivation of toxicity values for RA use EPA RAGS Categories for Carcinogens EPA 4 (5)-steps for performing Tox Assessment Presentation of toxicity values/profiles Regional supplemental guidance 3

4 Toxicity Assessment based on Toxicology All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy. Paracelsus ( ) 4

5 EPA RAGS Chapter 7 Note: Toxicity Assessment may/should be performed in parallel with Exposure Assessment. 5

6 Toxicity Assessment based on Toxicology Toxicology is the study of the adverse effects of chemicals on living organisms. Note: chemicals don t have to be environmental contaminants. Lots of naturally occurring chemicals can exert an adverse effect, e.g. snake venom. Toxicology is a hodge hodge-podge of sciences from many disciplines medicine chemistry biochemistry many others 6

7 ADME Basis of Toxicology is ADME Absorption Distribution Metabolism (also known as Biotransformation) Excretion (also known as Elimination) any substance has a unique ADME pattern chemicals with similar ADME characteristics exert similar adverse effects -- basis of predictive toxicology ADME variation exists between species and individuals 7

8 8

9 Absorption Crossing of an exchange boundary (skin, GI tract, lungs, ) exposure routes ingestion inhalation dermal contact direct radiation exotic routes (not usually quantified in risk assessment) injection ocular contact NOTE: don t confuse exposure routes with exposure pathways 9

10 Distribution How chemicals are transported and distributed throughout the body typically transported by bloodstream, but also lymphatic system final distribution dependent upon characteristics of chemical Bone: some chemicals are bone-seekers : Pb, Sr,, Al Fat: lipophilic chemicals: DDT, PCB Brain: only things able to traverse Brain Blood Barrier: glucose time-dependency to reach distribution some chemicals pass right through 10

11 Metabolism Body acts on the chemical and changes it Why? Food uptake - make building blocks, obtain energy Detoxification mechanisms - have evolved defense strategies some metabolic actions can reduce toxicity Toluene (potent) is oxidized into benzoic acid (low potency) Other metabolic actions cause more problems Bromobenzene into bromobenzene epoxide (highly reactive) liver is the primary organ of detoxification (also prime target organ) 11

12 Excretion All chemicals eventually leave the body. In fact, the vast majority of our molecules that we had a few days ago, no longer are in our bodies (we are stardust ). Excretion occurs through kidney - urine GI tract - feces lungs - exhalation (e.g. VOCs) secretory glands - sweat, saliva, semen, milk Rate of excretion varies with the chemical very important characteristic residence time in body the longer the chemical has time, the more effect it can exert 12

13 Conditions of Exposure Important to realize that adverse effect is dependent on conditions of exposure ➊ size of dose (scale from non-toxic to supertoxic) amount of chemical needed to see an effect ➋ duration of dosing Acute -- single dose Subchronic -- up to 7 years of repeated dosing Chronic -- whole life exposure ➌ exposure route also important is timing of dose (biorhythm, sensitive times -- illness, pregnancy, etc. ) 13

14 Targets of Toxicity Different chemicals display different ADME patterns and act on different targets. Organs and organ systems Liver is the active detoxification organ. First to get afflicted. Liver is recuperative and most insults are reversible effects. Some are not: alcohol causes cirrhosis through fatty deposits. Cell types Nerve cells are favourite cell type targets for poisons, both natural and anthropogenic cobra venom is classified supertoxic with immediate toxicity 14

15 Targets of Toxicity (cont( cont.) Cellular components specific targets on or within cells proteins phospholipids RNA / DNA, e.g. mutagens affect the DNA of cells 15

16 Types of Toxicity Many different toxic endpoints e.g. hepatotoxins -- affect the liver for risk assessment, until recently only considered two (2) categories carcinogenic = cancer causing non-carcinogenic = systemic toxicity all endpoints that were not carcinogenic now additional EPA guidance available & also need to consider: Developmental toxicants (special category for teratogens) Mutagens Neurotoxicants Irritants 16

17 Mechanisms of toxicity Many different ways for chemicals to affect the normal homeostasis of the body and exert an adverse health effect. Free radical production certain classes of chemicals, as well as radionuclides Combination with enzymes inhibition or activation of key enzymatic processes Genotoxicologic mechanism interaction with DNA to cause alteration, e.g. UV Immunotoxicologic mechanism suppression of immune response 17

18 Interaction of Toxic chemicals in body We usually don t get exposed to just one chemical at a time. What happens when exposed to several chemicals simultaneously? Additive effect: = 5 EPA default assumption Synergistic effect: = 20 Potentiation: = 10 Antagonistic effect: = 1 or 2 + (-2) = 0 Currently, we are able to only perform additive risk evaluation => source of uncertainty. 18

19 Derivation of toxicity values for RA use Normally, risk assessors will NOT derive the toxicity values, but need to know where the limitations and uncertainties are. Most toxicity values are obtained from laboratory studies with rats/mice. Toxicologists expose several groups of rats to different doses of the chemical and observe for the particular toxic endpoint (adverse effect). Perform a dose-response assessment and graph data. 19

20 Derivation of toxicity values (cont( cont.) Typical sigmoidal dose-response curve Source: Online Toxicology Tutor from National Library of Medicine 20

21 Derivation of toxicity values (cont( cont.) Dose-response relationship (non-carcinogens) Source: Online Toxicology Tutor from National Library of Medicine 21

22 Derivation of toxicity values (cont( cont.) Threshold: that extrapolated concentration (dose) where any concentration (or dose) below does not cause an adverse effect LOAEL: lowest observed adverse effect level. That tested concentration (or dose) which still demonstrates a statistically significant adverse effect. NOAEL: no observed adverse effect level. That tested concentration (or dose) at which no statistically significant adverse effect can be demonstrated. NOEL: no observed effect level. Sometimes effects are observed that may not be related to the toxicological response. Caution: toxicity studies with only NOELs -??? 22

23 Derivation of toxicity values (cont( cont.) How to get from either NOAEL or LOAEL to RfD? EPA RAGS approach: Apply uncertainty factors. (could change if EPA accepts Benchmark Dose approach) Type Factor Human variability (intraspecies( intraspecies) 10x Extrapolation from animals to humans 10x (cross- or interspecies) Subchronic instead of chronic study 10x LOAEL instead of NOAEL 10x Incomplete database 10x Modifying factor 1 to 10x TOTAL: 100,000 to 1,000,000x 23

24 Derivation of toxicity values (cont( cont.) Calculation of RfD RfD = _NOAEL (or LOAEL)_ UF (1) x UF (2). X MF UF (1) The more uncertainty factors are needed, the smaller the number, thus, the HI will be higher. This approach is applicable to all threshold types of toxicity. Fundamental difference to Delaney carcinogenic approach. Up until 1997, EPA s paradigm of carcinogenicity was based on the Delaney clause, stating no amount of a carcinogen is safe, thus, no threshold. New guidelines allow for thresholds for carcinogens. CAUTION: Not accepted by everybody -- states lagging behind. 24

25 Derivation of toxicity values (cont( cont.) Dose-response relationship (carcinogens) Source: Online Toxicology Tutor from National Library of Medicine 25

26 Derivation of toxicity values (cont( cont.) Extrapolation Models for Nonthreshold effects Linearized multistage: multiple stages for cancer. Fits curve to the experimental data. Linear from upper confidence level to zero. One-hit: single stage for cancer: one molecule or radiation interaction induces malignant change. Multi-hit: several interactions needed before cell becomes transformed. Least conservative model. Probit: probit (log-normal) distribution for tolerances of exposed population. Appropriate for acute toxicity; may not be appropriate for cancer. 26

27 Derivation of toxicity values (cont( cont.) Extrapolation Models for Nonthreshold effects (cont.) Physiologically-based pharmacokinetic Incorporates pharmocokinetic and mechanistic data into the extrapolation. Data rich requirements and, while promising, are currently of limited availability. 27

28 Source: Online Toxicology Tutor from National Library of Medicine 28

29 EPA RAGS Categories for Carcinogens 29

30 EPA 4 (5)-steps for performing Tox Assessment Step 1. Gather toxicity information - qualitative and quantitative for substances being evaluated. What type of information? Toxicity Profile human data from epidemiological studies, occupational exposures animal data from controlled laboratory experiments provides the majority of our knowledge of chemical s action supporting data - biochemical, metabolic, cell culture tests, physiologically-based pharmacokinetic modeling Toxicity values from IRIS (EPA Integrated Risk Information System) or HEAST (Health Effects Assessment Summary Tables) 30

31 EPA 4 (5)-steps for performing Tox Assess. (cont( cont.) Step 2. Identify exposure periods for which toxicity values are necessary. Important: can t use subchronic RfDs for life-time exposures. Need to match the exposure duration under investigation with the correct toxicity value. Mostly EPA has chronic toxicity values available. The chronic values may be derived with 10x UF from subchronic laboratory animal studies. If use chronic tox value for subchronic exposure, may have an extra 10x UF; means risk results are 10x higher. 31

32 EPA 4 (5)-steps for performing Tox Assess. (cont( cont.) What does the risk assessor have to do? ALWAYS obtain the latest toxicity value from IRIS. If not available in IRIS, then try HEAST. If not in HEAST, need to consult with regulator. The regulator may point to other sources of tox values: EPA NCEA (formerly ECAO) EPA Criteria Documents ATSDR profiles Scientific literature review Actually, EPA in middle of transition of process for tox value selection (IRIS => NCEA => HEAST => other sources) Obtain toxicity profiles. EPA, ATSDR, or have toxicologist write. 32

33 EPA 4 (5)-steps for performing Tox Assess. (cont( cont.) Step 3. Determine toxicity values for non- carcinogenic effects. Using the risk scenario s exposure duration consideration, select the appropriate values. Step 4. Determine toxicity values for carcinogenic effects. Using the risk scenario s exposure duration consideration, select the appropriate values. Step 5. Summarize toxicity information. Prepare tables that show the toxicity value and information. 33

34 EPA RAGS Part D Sample Tox Info Presentation Table carcinogens 34

35 EPA RAGS Part D Sample Tox Info Presentation Table non-carcinogens 35

36 Regional supplemental guidance Chemicals without toxicity value use value of chemically and toxicologically related chemical best professional judgement otherwise strongly recommend contacting regulator AND keeping a record of agreed upon tox value Inhalation Toxicity values shows equations to convert from RfC and Unit Risk Dermal Toxicity values differentiation of chemicals based on absorption efficiencies 36

37 Regional supplemental guidance Toxicity of Dioxin and cpahs use TEF (Toxicity Equivalence Factor approach) Total Petroleum Hydrocarbons (TPH) provisional toxicity values (be careful about provisional values; can be revoked at any time without notice). Subchronic toxicity values (for children) Region IV does not consider subchronic RfDs protective for children Assessment of Lead use IEUBK (Integrated Exposure Uptake Biokinetic) ) model. 37