environmental health ii. toxicology shu-chi chang, ph.d., p.e., p.a. assistant professor 1 and...
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Environmental Health II. Toxicology
Shu-Chi Chang, Ph.D., P.E., P.A.Assistant Professor1 and Division Chief2
1Department of Environmental Engineering2Division of Occupational Safety and Health,
Center for Environmental Protection and Occupational Safety and Health
National Chung Hsing University
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
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
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
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.
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)
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
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
Pathways of exposure and excretion (4)
Pathways of exposure and excretion (5)
Pathways of exposure and excretion (5)
Biological accumulation and magnification
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
Acute toxicity studies
Gaussian distribution
Acute toxicity studies
Cumulative percentage
Which one is more toxic?
Acute toxicity studies
LD50: Lethal dose for half of the exposed population within a certain period of time.
Synergistic and antagonistic effects
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.
Outcomes
Typical Target organs Effects Dose-effect and dose-response relationships Maximum tolerated dose Some may not be observed
Reproduction Disease Decreased longevity
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”
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
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)
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.
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.
Dose response curve
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
Steps1. Identification of all adverse effects2. Establishment of dose-response relationship3. Establishment of chemical database4. Decision of the data relevance5. Use the data to establish exposure limit for
human
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
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?
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