Toxicology
Mathieu Orfila
- "Father of Toxicology" - Contributed to the foundation of forensic toxicology (Arsenic)
Paracelsus
- "Founder of Toxicology" - The dose-response relationship - Target organ specificity of chemicals - said the dose makes the poison (Example: Hyponatremia: water intoxication due to low salt balance)
Alice Hamilton
- 1869-1970 - First woman appointed to Harvard faculty.Esteemed career in occupational and environmental health - very influential voice on early committees addressing lead and other hazards. - Addressed many toxic exposures well into 20th century.
Rachel Carson
- 1907 - 1964 - Silent Spring
Sarin
- Developed 1938 - result of pesticide researchBecame standard in chemical weapons arsenals - Used in Iraq-Iran war - 1993 Chemical Weapons Convention - Inhibits cholinesterase - nerve toxin - Same mechanism as organophosphate pesticides LD50 (mouse - injection): 0.172 mg/kg Malathion (mouse): 1000-10,000 mg/kg - Treatment: Atropine; Pralidoxime (antagonist)
Syrian Forensic Toxicology Investigation (Sarin)
- Environmental sampling - Biological sampling - Exposure/Risk Assessment - Patient Sx Review - SLUDGE - Autopsy - Long-term follow-up if possible Basic Principles of Environmental Health
Fields Within Toxicology
- Environmental toxicology - Reproductive toxicology - Developmental toxicology - Forensic toxicology - Clinical toxicology - Regulatory toxicology
Animal Bioassays
- Short lifespan in rodents makes testing practical - Tiered process of standardized tox studies - Acute toxicity testing- LD50 - Subchronic rodent bioassay - Chronic rodent bioassay
Bernardino Ramazzini
- The Father of Occupational Medicine - De Morbis Artificum Diatriba (Diseases of Workers)
Sir Percival Pott
- Tracked the occurrence of scrotal cancer - Demonstrated that cancer can be caused by an environmental carcinogen (benzo(a)pyrene)
effects of chemical mixtures
- additive - synergism - potentiation - antagonism
limitations of animal toxicology studies
- extrapolating across species to humans - extrapolating high exposures to actual human exposures that are lower - accounting for variation in human living conditions (nutrition, temperature, other exposures), genetic variation - accounting for interactions between chemicals
absorption, distribution, metabolism, excretion
ADME stands for
poisons
Agents capable of producing an adverse response in a biological system
600, 1000, 5000
Carbon Dioxide Standards • normal outdoor level: 350 - 450 ppm • acceptable levels: < ____ ppm • complaints of stuffness and odors: 600 - 1000 ppm • ASHRAE and OSHA standards: ______ ppm • general drowsiness: 1000 - 2500 ppm • adverse health effects may be expected: 2500 - 5000 ppm • maximum allowed within a 8 hour working day: _______ - 10000 ppm • maximum allowed within a 15 minute period: 30000 ppm
xenobiotics
Chemical substances that are foreign to the biological system
Phase II reactions
Conjugation Example: Glutathione (GSH). Metabolites often less active.
toxicity
Factors that influence _________ - Route of entry into the body - Duration of exposure - Interactions between multiple chemicals - Individual sensitivity/susceptibility
individual susceptibility
Factors that influence toxicity - Age - Sex - Race - Health status - Exercise - Genetic make-up - History of previous exposures
Phase III reactions
Further modification and excretion
Experimental studies in animals, Tissue culture, studies using cells, Human studies
How do we know what's toxic and at what levels?
0.3 mg/kg
Lets say the water has 30 mg of methyl ethyl death dissolved in it. I drink it all. How much methyl ethyl death did I ingest? So the dose was? If I weigh 100 kg, how many mg/kg? 30/100 = ________ _____
LOAEL (lowest observed adverse effect level)
Lowest data point at which there was an observed toxic or adverse effect
toxic substances
Materials that have toxic properties
Phase I reactions
Modification (oxidation, reduction, hydrolysis) Example: Cytochromes P450 (CYPs). Metabolites often more active
lightly toxic
Oral acute LD50for rats(mg/kg): 5,000-15,000 (ex. ethanol)
Extremely toxic
Oral acute LD50for rats(mg/kg): 5-50 (ex. Picrotoxin)
Highly toxic
Oral acute LD50for rats(mg/kg): 50-500 (ex. DDT)
moderately toxic
Oral acute LD50for rats(mg/kg): 500-5,000 (ex. NaCl)
Supertoxic
Oral acute LD50for rats(mg/kg): <5 (ex. Dioxin, botulinum toxin)
practically non-toxic
Oral acute LD50for rats(mg/kg): > 15,000 (ex. water)
threshold
The ____________ of a dose-response curve
dose
The amount of a chemical or physical agent that comes into contact with a living organism Usually expressed as mg/kg-day
Biotransformation (metabolism)
The chemical alteration that a substance undergoes in the body. - Bioactivation - Detoxification - Distribution - Excretion
NOAEL (no observed adverse effect level)
The highest exposure level at which there are no biologically significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control.
Bioactivation
The metabolic activation of xenobiotic compounds into reactive , toxic compounds.
Detoxification
The physical process of freeing the body of an addictive substance
Dose-Response Relationship
The relationship between exposure to a chemical and the spectrum of effects caused by the chemical.
toxins
Toxic substances produced by living organisms
toxicants
Toxic substances that are man-made or result from human activity
organ specific
Types of __________ __________ toxic effects - Hepatotoxicity -Cardiovascular toxicity - Nephrotoxicity - Lung toxicity - Neurotoxicity - Immunotoxicity - Reproductive toxicity
ppb
We often measure chemicals in blood or urine in the ____ range. 1 ____ is like one pancake in a stack of pancakes 4,000 miles high. 1 ____ is like one drop in a backyard swimming pool. Some drugs and hormones act in the ____ range, or lower
Ingestion, inhalation, dermal contact
What are the Routes of Exposure Influence Toxicity?
Salivation, Lacrimation, Urination, Defecation, Gastrointestinal upset, Emesis
What does sludge stand for? (sarin effects)
Linear
___________ dose response curve
U-shaped
____________________ dose response curve
Toxicology
____________________ is the study of the adverse physiologic effects of chemical, physical or biological agents on living organisms, including the prevention and treatment of such adverse effects.
clinical trials
a type of human study administration of chemicals to humans with careful clinical observations and laboratory measurements
Duration of Exposure
acute, subacute, subchronic, chronic
Local effects
damage at the site where a chemical first comes into contact with the body
dose-effect curve
depicts the magnitude of a drug effect by dose
Lethal Dose 50 (LD50)
dose which is lethal to 50% of test subjects
chronic exposure
exposure for more than three months
subacute exposure
exposure for one month or less
subchronic exposure
exposure for one to three months
toxic dose
population dose
target effects
some chemicals may confine their effects to specific organs
absorbed dose
the actual amount of exposed dose that enters the body
exposure dose
the amount of a xenobiotic encountered in the environment
Additive
the combined effect of two or more chemicals is equal to the sum of the individual effects
Synergistic
the combined effect of two or more chemicals is greater than the sum of their individual effects Cancer Risk Smoking: 11x unexposed Asbestos: 6x unexposed Smoking+Asbestos: 59x unexposed
system effects
the influences of the structure and/or composition of a system on the behavior of the members of the system
administered dose
the quantity administered usually orally or by injection
total dose
the sum of all individual doses
TD50
toxic dose in 50% of the population
TD0
toxic to 0% of the population
TD10
toxic to 10% of the population
TD90
toxic to 90% of population
Antagonism
two chemicals interfere with each other's actions or one interferes with the action of the other
Epidemiology
type of human study Populations exposed in the normal course of life or occupational or accidental exposures
acute exposure
usually a single exposure for less than 24 hours
Potentiation
when a non-toxic chemical causes another chemical to become more toxic (Benadryl/Codeine)
