Risk Assessment and Analysis Flashcards
(see risk assessment in context of agriculture)
(see risk assessment in context of agriculture)
father of toxicology who said all things are poison and nothing is without poison only the dose permits something to be not poisonous
Paracelsus
mother of toxicology; an applied toxicologists who had poisons in her jewelery which caused death to her suitors
Lucrezia Borgia
legal definition of poison
see table of ld for humans
chemical that has a lethal dose (LD50) less than or equal to 50 mg of chemical per kg of body weight
® 50 mg/kg is approximately ¾ tsp. for the average adult, and
about 1/8 tsp. for the average 2-year-old
How does dose of poison play a role in risk assessment?
® Relationship of dose and size: a smaller person would require a smaller dose of poison for it to be lethal, as
compared to a larger person
® Children
this is used for inhalation work; determined by exposing several groups of animals (e.g. rats or
mice) each to a different air concentration of chemical for a onehour
period, then they are observed for a 14-day period
lethal concentration 50
x-axis and y-axis of dose-response curve
- X-axis: dose/concentration (mg/kg)
* Y-axis: response
How much of a particular compound kills 50% of the
population
LD50
A wider range of toxicity indicates (preferred)?
a narrower margin of error = need for ra
second part of risk assessment
toxicity assessment
This was recognised first in occupational illness
chronic toxicity
certain trades with poorer health as noted by greek physicians
mining, metallurgy, pottery
Hippocrates described what? (re: toxicity assessment)
severe colic in men who extracted metals (lead poisoning)
Poisoning which Pliny wrote about
mercury poisoning in miners from quicksilver mines of Spain
Ways of exposure to lead
- Water supply – in old pipes
- Naturally occurring lead
- Lead as a contaminant – in air and water
- In USA, especially the North America, lead was used in painting houses
Refers to the ability of a substance to do systemic damage as a result of a one-time exposure of relatively short duration
Acute toxicity (inversely related with LD: mgchemical/kg of body weight)
what does ld 0 and ld100 mean?
- LD0 = no resultant deaths
- LD100 = death of the entire population
Refers to the harmful systemic effects produced by long-term,
low-level exposure to chemicals
Chronic toxicity
synonym for toxicity
hazard (more complex due to involvement of conditions of use)
Two components of hazard
• Inherent ability of the chemical to do harm by virtue of its explosiveness, flammability, corrosiveness, toxicity, etc.
• The ease with which contact can be established between
the chemical and the object of concern
pathway by which chemical gets into body
routes of exposure
three major routes of exposure
dermal entry (most common way; skin = 20 sq ft effective barier)
inhalation (2nd most common)
oral (through ingestion)
T or F: lungs are very effective barrier to chemicals
false, poor (lung surface: 750 sq ft has delicate one cell thick membrane wc allows easy passage of o2 and other harmful chemicals as well from alveolar space to blood)
collective term for the damage to lung surfaces caused by foreign objects
pneumoconiosis
causes: asbestos, silica, dust, cotton, coal, sugar cane pulp
Chemicals that enter body are absorbed through where?
GI tract (can occur from mouth to rectum; majority: SI)
Where is nitroglycerine usually absorbed through?
mucus membranes of the mouth, that is why it is taken and placed under the tongue.
This is absorbed rapidly in stomach as well as intestine
ethyl alcohol (effects seen imm.; food in stomach delays its effects)
Other routes of entry of chemicals
- Intravenously
- Subcutaneously
- Intramuscularly
- Intraperitoneally
- Intradermally
Six kinds of toxicity when dose time and route factors are combined
® Acute dermal ® Chronic dermal ® Acute inhalation ® Chronic inhalation ® Acute oral ® Chronic oral
chemical that is equally toxic by all three routes of exposure
organophosphate pesticide parathion (highly acute toxic; exhibits cholinesterase enzyme wc deactivate choline esters)
In OPP toxicity mech, what happens when cholinesterase is inhibited?
acetylcholine is not deactivated (continued stimulation of PNS)
OTHER FACTORS THAT INFLUENCE TOXICITY OF A CHEMICAL SPECIES
animal models (toxicity vary among species)
age
sex
What converts hemoglobin to methemoglobin?
nitrobenzene
T or F: rats cant vomit
true
T or F; in animal models, Similarities ease the process while differences require a different animal’s response to toxicity to accurately represent
man’s toxicity to a compound.
true
carcinogenic = cancer in animal species at any level of exposure
use of animal data to human data dates back to 1958. Why?
Food Additives Amendments Act (Delaney Amendment)
example of age affecting toxicity
DDT is not acutely toxic to newborn rats; however, it becomes increasingly toxic as the rats mature. Adult LD50 is 200-300mg/kg
• The organophosphate parathion is more acutely toxic to newborn rats than adult rats due to their differing capability to metabolize foreign chemicals
The differing capability to metabolize foreign chemicals of newborn rats and mature rats is due to
liver microsomal enzyme system.
example of sex affecting toxicity
Male rats are 10x more sensitive to liver damage than female rats from chronic exposure to DDT (sex diffs due to hormone activity)
What can limit the difference between sex?
castration or hormone administration (Castrated male rats had virtually equal sensitivity to liver
damage as compared to females upon chronic exposure to
DDT)
T or F: humans are more sensitive than test animals
true
margin of safety of fda
100-fold (no adverse effect = 100 ppm, maximum dietary concentration= 1 ppm)
considered the initiating event in carcinogenesis
mutation (change in the genetic code that result in a change of the message)
Abnormalities in developing organisms during uterine life
teratogenesis
statistics on teratogenesis
- Congenital malformations in U.S.: 2 in 100 live births
* 20% of all pregnancies do not go to term as a result of spontaneous abortion
examples of teratogenesis
thialidomide
diethylstilbestrol
Prescribed between 1940 and 1970 to prevent miscarriage in high-risk pregnancies; cases of vaginal adenocarcinoma in women ages 16-20
were linked to fetal exposure through maternal DES ingestion early in the pregnancy.
diethylstilbestrol
1 in 1000 pregnancies were exposed
effects of diethylstilbestrol
- Females: carcinomas (vaginal, cervical), uterine abnormalities; higher risk for ectopic pregnancies, miscarriage and preterm labor and delivery
- Males: some form of abnormal genitalia (microphallus, testicular varicoceles, hypospadias), epididymal cysts,
undescended testes
§ Marketed outside U.S. (1950s) as a mild sedative to combat nausea and morning sickness but withdrawn from market in 1961
Thialidomide
(Not all animal species tested produced reactions to thialidomide similar to humans; Risk of teratogenic effects only appear when drug is taken during a specific time period 34-50 days into preggy after beginning of last menstrual period)
effects of thialidomide
Risk of ≥20% of baby with phocomelia, missing ears,deafness
Recent uses of thialidomide
- Approved treatment and control of leprosy-associated skin sores
- Laboratory tests show its ability to inhibit HIV replication and reverse AIDS-related cachexia
- Treatment of non-microbial aphthous mouth and throat
ulcers
formula for risk
risk = hazard x exposure
four steps for risk assessment
- Hazard identification
- Toxicity assessment – dose/response
- Exposure assessment
- Risk characterization
(sometimes: 5. Risk management, 6. Risk communication)
see risk assessment diagram
see risk assessment diagram and xenobiotic exposure and lifetime risk based on employment
see example of risk assessment
see example of risk assessment
questions to ask in hazard id
- What is the chemical of concern?
- What’s been spilled, leaked, emitted, etc.
- Does the chemical undergo transformation?
- If transformed, which product is of most concern?
- If mixture, which chemical is the most toxic?
steps involved in exposure assessment
• Identify hazard • Determine likely exposure pathway • Calculate concentration • Calculate dose • Determine applicable time • Exposure Media ® Air ® Soil ® Water ® Food
factors affecting ingestion
® Quantity of water ingested
§ Climate
§ Physiological factors: age, weight, gender
§ Level of physical exertion: resting, exercising, working
® Ability of the body to absorb contaminant
§ Chemical
§ Target organ
® Concentration of chemical in water
average consumption of water by a person/day
2 liters
commonly inhaled
water aerosols (<5 micrometers)
transfer of chemicals through inhalation is usually through
showering
post bathroom time
remainder of house (miscellaneous)
factors affecting INHALATION
® Concentration in air
® Physiological factors: breathing rate, age, weight, gender
® Exposure duration – hours, day
® Exposure frequency – day, week
factors affecting INDOOR inhalation
® Ventilation rate § Shower § Post shower bathroom time § House – geographic location ® Time per day spent in house ® Number of people in house – water use
Factors affecting dermal absorption:
- Permeability of skin to chemical in question (Unique property of chemical lipophilicity, Usually based on animal measurements)
- Concentration of chemical – air, water
- Duration of contact
- Exposure media – air, water, soil
- Exposed skin surface area (Physiological: age, weight, gender; Activity during contact)
time averaging of toxicity includes classification into
• Daily • Yearly • Lifetime ® 70-75 years ® Standard U.S. EPA • Cumulative ® Total dose over entire exposure period • Other ® Based upon exposure scenario (e.g. weekly)
(see gen modelling principles)
(see gen modelling principles) basa pa gurl
