Spectrum of Toxic Effects

Question 1

Local Effects

Answer 1

• uncommon compared to Systemic
• Corrosive chemicals on skin (e.g strong acids and bases) ie. strong acid that can burn a hole through your skin
• Irritating gases and vapours in respiratory tract (e.g. ammonia and chlorine gas)

Question 2

Systemic Effects

Answer 2

• Xenobiotic must be absorbed into systemic circulation and distributed to organs/tissues
• Many xenobiotics preferentially cause toxic effects in one or a few specific organs (“target organs”)
• Target organ may not always have the highest xenobiotic concentration
  must get into bloodstream to be ready to distribute and excrete

Question 3

Reversible effects

Answer 3

• Effects disappear after exposure ends
• Usually short-term and/or low dose exposures
• effects go away

Question 4

Irreversible effects

Answer 4

• Effects persist or even worsen after exposure ends
• e.g carcinomans, teratogenic effects (damage from mother to fetus), neuronal damage, liver cirrhosis
  -usually long-term and/or high dose exposures
• doesn’t go away or get worse over time

Question 5

Immediate effects

Answer 5

Acute
- TImeframe minutes to days (short term)
- e.g. cyanide (blocks electron transport chain-cannot produce ATP = death), carbon monoxide poisoning - cause of death = no ATP being produced

Question 6

Delayed Effects

Answer 6

Chronic
- Timeframe months to years
- e.g. cancer develops 10-20 years after exposure, both in individuals and also potentially their offspring - recall diethylstilbestrol (DES) used to prevent miscarriage in women- daughters from these mothers have reproductive cancers at around 20 years old
- Illustrates the need to conduct long-term toxicological studies and transgenerational toxicological studies

Question 7

Morphological Effects

Answer 7

• Gross or microscopic effects on tissues; commonly irreversible
• e.g. thalidomide teratogenicity - prevent morning sickness in first trimester - blocked development of arms and legs in fetus
• e.g. histopathological effects on liver cells

Question 8

Functional Effects

Answer 8

• e.g. liver or kidney function, reproduction
• Generally reversible effects
  function can be damaged - by binge drinking - reversible liver damage

Question 9

Biochemical effects

Answer 9

• Virtually all toxic effects are initiated by an alteration in biochemical or molecular processes (e.g. receptor binding, enzyme inhibition)
• Such Biochemical effects are often used as biomarkers that serve as early indications or “markers” of toxic effects
• Note that such biochemical effects are reversible and do not necessarily indicate an adverse morphological or functional effect
  measuring response can help predict if toxicity will occur

Question 10

Allergic Effects - Hypersensitivity Reactions

Answer 10

• Require prior exposure; xenobiotic can react with protein to produce antigen, antibodies are produced and illicit immune response
• e.g bee venom or nuts can cause severe allergic reaction

Question 11

What is sick building syndrome

Answer 11

when you are allergic to perfumes or smells, multiple chemical allergy syndrome
- new car smell, glues and fire repellent substances etc.

Question 12

Allergic effects - Autoimmune reactions

Answer 12

• xenobiotics can initiate autoimmune responses/diseases such as systemic lupus erythematosus

Question 13

Idiosyncratic effects

Answer 13

• Genetically based abnormal reactivity to a xenobiotic with no known cause - don’t know why they occur, just know its due to genetics
• e.g. certain drugs can produce rare, idiosyncratic reactions

Question 14

Graded effects

Answer 14

• Continuous responses e.g. effects on body weight, food consumption, enzyme activity
• initiate number of responses - continuous data

Question 15

Quantal effects

Answer 15

-all or nothing responses
- E.g mortality, cancer
- we will cover graded and quantal effects later when we talk about dose-response relationships

Question 16

Systemic effects and target organs
Question: why are certain organs targets of xenobiotics?

Answer 16

generally due to greater susceptibility or higher xenobiotic concentration, although the explanation is not always clear

Question 17

Increased susceptibility

Answer 17

of organ, e.g. carbon monoxide (CO) poisoning in highly aerobic tissues (heart and brain) with little anaerobic capacity

Question 18

Preferential distribution

Answer 18

e.g. higher blood flow to liver and kidney; MeHg able to cross BBB (blood brain barrier)

Question 19

Selective uptake

Answer 19

e.g. cadmium (cd) preferentially accumulates in kidney tubule cells due to high expression of Cd-binding protein - increased concentration of cadmium

Question 20

Bioactivation

Answer 20

to reactive metabolites e.g. liber (liver big target organ) (CYP enzymes) - high bioactivation in liver

Question 21

insufficient repair,

Answer 21

e.g. neuron damage in central and peripheral nervous system - peripheral neuropathy