PH 201: Chapter 3

When are animal models used in toxicologic testing?

- when highly controlled and standardized conditions are desired - preliminary testing of pharmaceuticals, pesticides, and substances that may present toxic hazards to human subjects

What must exposure assessment take into account when referring to a toxic substance?

- where exposure occurs - how much exposure occurs - how substance is absorbed by body

Two factors of risk according to Slovic

1. dread risk 2. unknown risk fig. 3-5

what are the two types of dose-response curves?

1. for the responses of an individual to a chemical 2. for the responses of a population

Steps in risk assessment

1. hazard identification 2. dose-response assessment 3. exposure assessment 4. risk characterization fig. 3-6

field of toxicology comprises approximately ___ areas

9

indirect effect

change in function of body's biochemical processes

It still remains unclear whether ______________ exposures to ___________ chemical agents in the environment occur at high enough ___________ to affect human health

chronic; toxic; doses

additive

combination of two chemicals produces effect is equal to their individual effects added together

describe an application of LD50

compare the toxicities of chemicals (whether one chemical is more or less toxic than another)

local effects

damage at the site where a chemical first comes into contact with the body

synergism

indicates that combined effect of exposures to two or more chemicals is greater than the sum of their individual effects

A dose-response relationship is one of the ___________________- used to assess the ______________ effect of a suspected ________________ upon a health _____________________

indicators; causal; exposure; outcome

Chemicals can enter the body __________________ or _____________________

intentionally; unintentionally

biomarkers

involve changes in genetic structure that are thought to be the consequence of an exposure ex: sister chromatid exchange

risk

involves likelihood of experiencing an adverse effect

long ________________ for many health events studied in environmental research makes _____________________ of the effects of ____________________ to toxic substances a methodologically difficult problem

latency; detection; exposures

meaning of risk varies also between ________ persons and ___________________

lay; professionals

assessment of available evidence

lays foundation for the problem of complexity

Environmental scientists have had increasing concerns over _________-term effects of ________-level exposures to toxic substances

long; low

toxic substance

material that has toxic properties

measures of lethality

may not describe fully a chemical's spectrum of toxicity ex: chemicals with low acute toxicity may have other effects such as carinogenicity or teratogenicity

dose-response assessment

measurement of 'the relationship between the amount of exposure and occurrence of unwanted health effects'

One aspect of toxicology is to examine the __________________ by which chemicals produce toxic effects on ____________ organisms and their tissues

mechanism; living

Most exposures are to ______________ chemicals

multiple

substances with low toxicity

must be ingested in large amounts in order for them to have toxic effects

After obtaining toxicologic information on the ________________ and ________________ effects of a chemical we want to determine the _________ to health the chemical represents

nature; health; risk

Spectrum of effect can range from _____ effect when dose is ____ to death when the dose is increased to _____________ level

no; 0; toxic

contact

occurrence of two events at same location and same time

dread risk

perceived lack of control, dread, catastrophic potential, fatal consequences, and inequitable distribution of risks and benefits

Response could be measured as the ___________________ of ________________ animals showing a particular effect, or it could reflect the effect in an ____________________ subject

percentage; exposed; individual

chemical idiosyncrasy

person has either extreme sensitivity to low doses of chemical or insensitivity to high doses

Internal dose

portion of a substance that becomes internalized in the body through ingestion, absorption, and other means

biologically effective dose

portion of internal dose that is required to cause a health outcome

exposure assessment

procedure that 'identifies populations exposed to the toxicant, describes their composition and size, and examines roots, magnitudes, frequencies, and durations of such exposures'

Risk assessment provides _____________________ or _____________________ estimation of likelihood of adverse effects that may result from ____________________ to specified health hazards or from absence of _______________________ influences

qualitative; quantitative; exposure; beneficial

administered dose

quantity of a substance that is administered

toxic agent

refers generally to a material or factor that can be harmful to biological systems

dose-response relationship

refers to a type of correlative relationship between 'the characteristics of exposure to a chemical and the spectrum of effects caused by the chemical'

threshold

refers to lowest dose at which a particular response may occur

sister chromatid exchange (SCE)

refers to reciprocal exchanges of DNA between pairs of DNA molecules

latency

refers to time period between initial exposure and measurable response

Food and Drug Administration (FDA)

regulates randomized controlled clinical trials

developmental toxicology

researches effects of natural and man-made chemicals on prenatal development (teratogens)

toxicologist

scientist who has received intensive training in order to investigate in living organisms 'the adverse effects of chemicals... and assess the probability of their occurrence'

coalitive interaction

several agents that have no known toxic effects interact to produce toxic effect

toxic substance can be a ________________ toxic chemical or a _______________ of toxic chemicals

single; mixture

Effects of a dose is related to body ________ of a subject

size

contact with skin generally produces ______________ response

slowest

target organ effects

some chemicals may confine their effects to specific organs ;most common organs affected are liver, lungs, heart, kidneys, brain and nervous system, and reproductive systems

potentiation

when one chemical that is not toxic causes another chemical to become more toxic

Dose is indicated along the _______-axis and response is shown along the _______-axis

x;y

different ways of describing a dose

- exposure dose - absorbed dose - administered dose - total dose - external dose - internal dose - biologically effective dose

what does the nature of a toxic effect depend upon?

- innate toxicity of chemical - whether chemical impinges upon a somatic location as a consequence of the route and site of exposure

types of direct effects

- local effects - systemic effects - target organ effects

Examples of indirect adverse effect

- modification of an essential biochemical function - interference with nutrition - alteration of physiological mechanism

what other factor affects the effect of exposure?

- person's sensitivity to chemical (ex: ability to metabolize chemical)

Subjects for testing the toxicity of chemicals

- volunteers who have had normal or accidental exposures - animals exposed in vivo experiments - cells derived from human, animal, or plant sources in vitro

data collected from employment records

- personal identifiers to permit record linkage to Social Security Administration files and retrieval of death certificates - demographic characteristics, length of employment, and work history with the company - information about potential confounding variables, such as employee's medical history, smoking habits, lifestyle, and family history of disease

inorganic toxins

- refers to specific chemicals, such as minerals, that have not been extracted from living organisms and do not follow the structure of a toxin derived from a living organism - usually small molecules

areas of toxicology

- regulatory - forensic - clinical - environmental - reproductive - developmental

What affects the concentration and toxicity of the chemical

- route of entry into body - received dose of the chemical - duration of exposure - interactions that transpire among multiple chemicals - individual sensitivity

hazard identification

'examines evidence that associates exposure to an agent with its toxicity and produces a qualitative judgement of the strength of that evidence...'

hazard

'inherent capability of an agent or situation to have an adverse effect. A factor or exposure that may adversely affect health'

exposure

'proximity and/or contact with a source of a disease agent or harmful effects of the agent may occur'

dose

'the amount of substance administered at one time'

toxicity

'the degree to which something is poisonous' ** related to a matter's physical and chemical properties

What is a dose-response relationship with respect to the population?

'the relationship of observed outcomes (responses) in a population to varying levels of a protective or harmful agent...'

antagonism

'two chemicals administered together interfere with each other's actions or one interferes with the action of the other...'

LD50

(lethal dose 50); 'dosage (mg/kg body weight) causing death in 50% of exposed animals'

terms that describe duration of exposure

- acute - subacute - subchronic - chronic

Describe the population dose-response curve

- at beginning of curve, there is a flat portion suggesting that at low levels an increase in dosage produces no effect = subthreshold phase - after threshold reached, curve rises steeply and progresses to linear phase - at linear phase, increase in response proportional to increase in dose - curve flattens out when maximal response is reached

What kinds of information can dose-response relationship provide?

- causal association between a toxin and biological effects - minimum dosages needed to produce a biological effect - rate of accumulation of harmful effects

Examples of direct adverse effect

- cell replacement, such as fibrosis - damage to enzyme system - disruption of protein synthesis - production of reactive chemicals in cells - DNA damage

risk assessment

'a process for identifying adverse consequences and their associated probability' 'the process of determining risks to health attributable to environmental or other hazards'

basic assumption of toxicology

'all substances are poisons... the right dose differentiates a poison from a remedy'

chemical allergy

'an immunologically mediated adverse reaction to a chemical resulting from previous sensitization to that chemical or to a structurally similar one'

poison

'any agent capable of producing a deleterious response in a biological system'

risk management

'consists of actions taken to control exposures to toxic chemicals in the environment'

__________________ of exposure assessment data determines __________________ of risk assessments

Quality; accuracy

toxicology

by definition, the science of poisons 'the study of the adverse effects of chemicals on living organisms'

_______________ may not occur if chemical is ________________ before the next ________________ happens

accumulation; excreted; exposure

Acute exposures may produce __________ effects that __________________ rapidly

acute; disappear

How quickly a chemical produces ____________ and other effects depends on ________ and ___________ of exposure

acute; site; route

risk research

addresses the identification and management of situations that might result in losses or harm, immediate or delayed, to individuals, groups, or even to whole communities or ecosystems, often as a result of the interaction of human activities with natural processes

systemic effects

adverse effects associated with generalized distribution of chemical throughout body by bloodstream to internal organs

target organ toxins

affect specific parts of the body

Factors that affect individual response to toxic substance

age, sex, race, health status genetic background use of medications consumption of alcohol pregnancy status

exposure dose

amount of a substance encountered in the environment

absorbed dose

amount of a substance that is available to the internal organs of the body

Specific examples of xenobiotics

antibiotics dioxins PCBs

how is dose expressed in practice?

as a concentration of a substance in the body ex: concentration per mL of blood

Why is human exposure assessment weak?

available methods are unable to provide adequate quantitative information regarding how much humans are exposed to toxic substances as well as specific kinds and patterns of exposure

Some environmental studies used ________________ that may be correlated with exposures to potential ___________________ and other chemicals

biomarkers; carcinogens

xenobiotics

broad class of chemicals that can produce developmental toxicity 'chemicals foreign to biological system'

What does it mean when a dose is fractionated?

broken up over a period of time

Chronic exposures may allow for ______________ of effects over time with resulting ______________________ of biological ______________

buildup; accumulation; damage

How does toxin production by microorganisms differ from disease causation?

by actual invasion and multiplication of microorganisms and consequent

organic toxins

denote substances originally taken from living organisms carbon-containing frequently made up of large molecules capable of being synthesized

carcinogen

denotes a chemical (or substance) that causes or is suspected of causing cancer

direct effect

denotes immediate impact upon cells and tissues of body or upon specific target organs

spectrum of toxic dose

describes the toxicity or hazards that are related to exposure to exposure to a particular chemical

risk characterization

develops 'estimates of number of excess unwarranted health events expected at different time intervals at each level of exposure' ** presents policy maker with synopsis of all info that contributes to conclusion about nature of the risk and evaluates magnitudes of uncertainties involved and major assumptions that were used

toxic effect can occur _________________ or _______________________

directly; indirectly

total dose

dosage acquired by adding together all of the individual doses

external dose

dose acquired by contact with contaminated environmental sources

Why are lethality tests becoming rare in research?

due to availability of less destructive methods of study

what are the implications of a fractionated dose?

effects may be different than those that transpire when a dose is administered all at one time

why is duration of exposure important?

effects of exposure to many chemicals may vary depending on whether exposure is minimal and takes place on single occasion for a short time period or is heavy and long-standing

Why does exposure need to take for a sufficient time duration and frequency?

effects of one-time exposure of short duration usually different from those of an exposure that happens on several occasions over long period of time

Evidence regarding hazards linked to toxic substances may be derived from study of health __________ among ______________ humans and animals

effects; exposued

environmental toxicology examines how _____________________ exposures to chemical __________________ may present ______ to biological organisms

environmental; pollutants; risks

process of human exposure assessment

examines 'the manner in which pollutants come into actual contact with the human body -- the concentration levels at the points of contact and sources of these pollutants making contact.'

reproductive toxicology

examines association between chemicals and adverse effects upon reproductive system

chronic

exposure for more than three months

subacute

exposure for one month or less

subchronic

exposure for one to three months

Related to the functions of toxicology are assessment of _______________________, ________, and __________________

exposure; risk; hazards

direct injection into bloodstream yields _____________ and ______________ effects

fastest; strongest

dose-response curve for individual

fig. 3-2 curve assumes a one-time exposure shows graded and increasing response as dose increases

population dose-response curve

fig. 3-3 displays a sigmoid shape (S-shaped) also a cumulative percentage response curve aka. quantal curve

most frequent sites of exposure to environmental chemicals

gastrointestinal tract, respiratory system, skin

unknown risk

hazards judged to be unobservable, unknown, new, and delayed in their manifestation of harm

Process of ______________ exposure assessment believed to be one of the _____________ aspects of risk assessment

human; weakest

genetically predisposed persons may be prone to chemical _____________________

idiosyncrasy

ecotoxicology

subfield of environmental toxicology special concern placed on release of toxic pollutants into environment ** focus on how these toxicants may become distributed within food chains and by measuring toxic responses made within a particular ecosystem to such pollutants

unintentional

such as accidents; environmental exposures

intentional

such as medical intervention

carcinogenesis

the potential to induce cancerous growth of cells example of delayed effect to exposure to chemicals

environmental toxicology

the study of how ecological systems (structure, dynamics, function, etc) are affected by pollutants

systemic toxins

those that affect entire body or multiple organ systems

how are randomized controlled trials conducted?

three phases begins with small groups of patients expansion to larger patient populations after earlier phase has demonstrated safety and efficacy of drug in question

toxicologists take into account the _________ dose, how ___________ each individual dose occurs, and the ___________ period during which the dosing occurs in order to describe the effects of a dose

total; often; time

toxicants

toxic substances that are man-made or result from human (anthropogenic) activity

Relevant evidence arises from __________________ and ___________________ investigations, and reflects the acquisition of ______________________ from many levels of _________________ understanding

toxicologic; epidemiologic; knowledge; scientific

toxin

usually refers to a toxic substance made by living organisms including reptiles, insects, plants, and microorganisms

acute

usually single exposure for less than 24 hours