1. Environmental Health II. Toxicology Shu-Chi Chang, Ph.D., P.E., P.A. Assistant Professor 1 and Division Chief 2 1 Department of Environmental Engineering 2 Division of Occupational Safety and Health, Center for Environmental Protection and Occupational Safety and Health National Chung Hsing University

2. Outline Short history Toxicology Source of information Pathways of exposure and excretion Conventional tests Multiple chemical sensitivity Endpoints of toxicological evaluations Molecular toxicology Exploration of animal data Establishing exposure limit Applying toxicological data to the environment

3. Short history about EH “ Silent spring ” by Rachel Carson in 1962 Major effects Awareness of the destruction of indiscriminate use of chemicals Environmental laws were made in 1970 ’ s “ Our Stolen Future ” Are We Threatening our Fertility, Intelligence, and Survival? - by Dianne Dumanoski, et al. in 1997 Major effects Awareness of the endocrine disruption caused by chemicals Inspired the research on Green Chemistry and Environmental Hormones

4. Toxicology Chemical usage 70,000 in common use and adding 200~1,000 annually Information is very limited especially when exposed to numerous different chemicals Toxicology is both a science and an art. Data gathering and projection

5. Source of information Epidemiological studies (next session) An array of lab studies In the past, toxic agents on animals as complete organisms Now, exploring the responses and effects of chemicals at the molecular level.

6. Pathways of exposure and excretion (1) Major routes Inhalation Ingestion Absorption Type Gaseous Particulate Nature and intensity of chemicals ’ effects Concentration Form Target organ How long (half-life)

7. Pathways of exposure and excretion (2) Absorbed chemicals Biological transformation Bioactivation Principal means of excretion Urine Liver lungs Sweat glands (less important) Note that GI is not a major route

8. Pathways of exposure and excretion (3) Effects Reversible and irreversible Could be acute or delayed: carcinogenesis Allergic reactions Other factors: species and strains, age, sex, and nutritional and hormone status. Physical factors: temperature, humidity, light cycles Social factors

9. Pathways of exposure and excretion (4)

10. Pathways of exposure and excretion (5)

11. Biological accumulation and magnification

12. Conventional tests for toxicity Acute toxicity studies A single or several administration of the chemical within 24 hours Chronic toxicity studies Short-term toxicity studies Repeated administrations, 10% life span 14-day and 28-day durations have been used Long-term toxicity studies Repeated administrations, entire life span

13. Acute toxicity studies Gaussian distribution

14. Acute toxicity studies Cumulative percentage Which one is more toxic?

15. Acute toxicity studies LD 50 : Lethal dose for half of the exposed population within a certain period of time. Synergistic and antagonistic effects

16. Short-term and long-term tests Short-term For more realistic situation Usually two or more species Most often rats and dogs Three levels of doses Long-term “ Acceptable intake ”, “ no observed adverse effect level ” Body weight, body size, food consumption Lab tests: hematological tests Postmortem examination: histological examinations, may measure the size of different organs.

17. Outcomes Typical Target organs Effects Dose-effect and dose-response relationships Maximum tolerated dose Some may not be observed Reproduction Disease Decreased longevity

18. Multiple chemical sensitivity Trace concentrations of a combination of chemicals Difficult to confirm Symptoms are usually subjective Exposure levels are orders of magnitude lower Symptoms appeared to have no relationship to known effects Observations in the past No observable adverse effect One or only a few target organs No difference in the nature of response Now for multiple chemical sensitivity No apparent safe level Multiple organ systems Individual difference in responses US Agency for Toxic Substances and Disease Registry (ATSDR) developed “ Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures ”

19. Endpoints of Toxicological Evaluations Carcinogenesis Initiator and promoter Activation of mutation of oncogenes or the inactivation of suppressor genes Ames test Reproductive toxicity Developmental toxicity Embryo, fetal death, growth retardation, malformation Thalidomide case Neurotoxicity Cognitive, sensory, motor impairment Immunotoxicity Suppress the immune function: AIDS Chemical AIDS

20. Thalidomide tragedy 1957 to 1962 in UK, Canada, Germany, Japan USA is not affected because FDA did not approve its usage Prevented morning sickness 12,000 babies who survived, with phocomelia (flipper-like arms or legs)

21. Molecular toxicity Need to understand the fundamental mechanisms Endpoints = Marker or indicators that signal the interaction in biological systems. Three types of markers Are a measure of response or dose Signal effects Are indicative of susceptibility Biomarkers enabled the use of DNA array for toxicological studies.

22. Extrapolation of animal data Two kinds Extrapolation from small animals to human From much higher dose within shorter time to much lower dose for long-term exposure Linear relationship (common assumption) May not be appropriate for dioxin, thyroid- type carcinogens, nitrolotriacetic acid, etc.

23. Dose response curve

24. Establishment of exposure limits (I) Two principles Use of human data whenever possible Use of surrogate chemicals or surrogate species only when scientific data showed evidence Steps 1. Identification of all adverse effects 2. Establishment of dose-response relationship 3. Establishment of chemical database 4. Decision of the data relevance 5. Use the data to establish exposure limit for human

25. Establishment of exposure limits (II) Safety factor X1/10: valid chronic exposure data existed on human and supportive chronic data were available on other species X1/100: no data on human but satisfactory chronic data existed for one or more other species X1/1000: chronic toxicity data were limited

26. Applying toxicological data to the environment Complications Different species or different groups of the same species may have different effects Some populations may occur in more than one form Synergistic and antagonistic Indirect effects may be greater that direct ones Nonlethal chemicals may have considerable ecological impact. Species other than human?

27. General Outlook Most carcinogens found by epidemiological studies or by physicians Cellular and molecular approaches Earthworms instead of rats and dogs Data and resources SARA ATSDR and USEPA National Priority List Pocket guide to chemical hazards Database Carcinogenicity (<20%), epidemiology (<10%), teratogenesis (<10%) Be aware of natural toxic chemicals