toxicology and drug interactions

LAST PHARM LECTURE given 4/23/2026

why does toxicology matter in dentistry?

safe use of drugs and chemicals

recognition of toxic effects in patients

awareness of environmental and occupational exposures

protection of patients and dental staff

understanding of mechanisms and risks of toxicity

prevention and initial management of poisioning

safety

condition of being secure from threat of danger, harm, or injury

toxicity

ability of a substance to cause harmful effects

hazard

inherent potential of a substance to cause harm (independent of exposure)

risk

likelihood that harm will occur under specific exposure conditions

dose-response relationship

effect increases with dose

threshold

lowest dose at which adverse effects occur

how is toxicity identified?

dose response relationship, LD50, target organ toxicity, mechanisms of toxicity

data used to define hazard and safe exposure levels

toxicology uses both graded (______) and quantal (______) responses, depending on what is being measured

dose intensity

dose frequency

LD50

dose causing death in 50% of the population

based on population (quantal response)

different individuals respond differently

used to compare relative toxicity

does not predict individual risk

lower the LD50, the ____ the toxicity

higher

NOAEL

highest exposure with no detectable adverse effect

LOAEL

lowest exposure where adverse effects begin, some effects have no clear threshold

dose determines the…

onset and severity of toxicity

what are some uncertainties with risk assessment?

extrapolation challenges: animal to human, high dose to lose dose, acute v chronic exposure

individual variability: different susceptibilities

role of mechanisms: helps interpret and extrapolate data

safety limits include uncertainty (safety) factors

risk assessment

hazard x exposure

exposure limits set to prevent adverse effects, based on NOAEL and safety factors

accounts for uncertainty- species difference, dose extrapolation, individual variability

translates toxicity into safe exposure levels

what are the major regulatory bodies in the US and what do they do?

EPA- environmental exposures like air, water, and pollutants

OSHA- workplace exposure limits

FDA- food, additives, medical products

what are the determinants of toxicity?

exposure factors- dose, route, duration/pattern

host factors- age and sex, liver and kidney function, genetics (intrinsic), disease states (acquired)

exposure + individual susceptibility + co-exposures

route of exposure

determines absorption rate and extent

influences onset, intensity, and distribution of toxicity

what are the major routes of exposure?

oral- first pass metabolism

inhalation- rapid systemic absorption

dermal- depends on barrier integrity

different routes = different systemic exposure for same substance

acute toxicity definition

adverse effects after single/short term exposure

acute toxicity core mechanism

high concentration exposure

direct, immediate cellular or receptor-mediated effects

minimal time for compensation or repair

acute toxicity typical mechanisms

CNS overstimulation or depression

enzyme inhibition (mitochrondrial toxicity)

membrane disruption / oxidative stress

acute toxicity clinical pattern

rapid onset, dose-dependent and predictable, often reversible if treated early

chronic toxicity definition

adverse effects from repeated or prolonged exposure

chronic toxicity core mechanism

cumulative damange and/or adaptive changes

may involve bioaccumulation or toxic metabolites

chronic toxicity typical mechanisms

persistent inflammation / oxidative stress

DNA damage → carcinogenesis

receptor downregulation / endocrine effects

chronic toxicity clinical pattern

delayed onset, often subtle early

may be irreversible

strongly influenced by duration and patient factors

effects develop gradually

t/f high acute toxicity = high chronic toxicity

false

how do host factors affect toxicity?

age- increase absorption, decrease detoxification in children

sex- hormonal and metabolic differences

liver and kidney function- decreased metabolism or elimination, increased toxicity

genetics- variability in metabolic enzymes

t/f same exposures can have different exposures across individuals

true

what are the types of toxic substances?

drugs- prescription and OTC

environmental chemicals- CO, metals, pesticides

occupational exposures- dental materials, gases

biological toxins- venoms, natural toxins

metals toxicity

bind to biologic molecules- interact with proteins and enzymes, enzyme inhibition

disrupt essential metal functions- can mimic ions like Ca2+ and alter cellular signaling

often affect multiple organs- but one system is most sensitive

common in environment and clinical settings- present in air, water, minerals, and some dental exposures

lead- what are major sources of exposure and key risk group?

lead based pain, contaminated dust/soil, drinking water, occupational exposure

children- pica or hand to mouth behavior

what are the consequences of lead exposure?

developmental effects (primarily neurologic, possible effects on growth)

chronic exposure can cause gingival lead line (burton line)

what are the mechanisms of toxicity of lead?

enzyme inhibition (-SH binding)- inhibits enzymes in heme synthesis, anema

disrupts Ca2+ signaling- mimics Ca2+ in neurons, alterns neurotransmitter release and synapse function, children are most sensitive to neurotoxicity

accumulation in bone and teeth- chronic exposure reservoir

tldr lead

heme inhibition, Ca2+ signal disruption lead to anemia and neurotoxicity

early effects of lead in children

>/= 3.5 ug/dl

neurodevelopmental defects

moderate levels of lead exposure in children

~10-20 ug/dl

cognitive and hearing impairment

high levels of lead exposure in children

>40-50 ug/dl

anemia, abdominal pain, nephropathy

severe levels of lead exposure in children

>70 ug/dl

encephalopathy, seizures

why is lead exposure more harmful in children?

neurodevelopmental vulnerability, higher absorption, behavioral exposure (they put everything in their mouth), greater dose per body weight

what is a safe level of lead exposure for children?

0, none, nada, gracie goose egg

is lead exposure is still an issue in the US?

kinda? it has dramatically decreased over time when removed from gas and paint but exposure still present in older housing and environment

elemental mercury

Hg^0

vapor (inhalation exposure)

found in dental amalgams

primarily affects CNS- tremor, irritability, memory impairment (erethism)

inorganic mecury

Hg+/Hg2+ salts

limited CNS penetration

primarily affects kidneys (± GI)- GI irritation/corrosion, nephrotoxicity

organic mercury

methylmercury

accumulates in fish

crossed BBB and placenta

primarily affects CNS (especially development)- severe neurotoxicity (paresthesias, ataxia, vision/hearing loss)

what is the mechanism of toxicity of mercury?

binds -SH group on proteins leading to enzyme dysfunction and cellular injury

disrupts neuronal function- impairs microtubules and neurotransmission

oxidative stress- neuronal damage

mercury exposure from amalgams

contains elemental mercury, low level vapor release during placement, removal, and chewing

primary route of exposure is inhalation to CNS exposure

chronic low level exposure to elemental mercury vapor

higher risk groups are pregnant, children, or pts with kidney diseases or neurological conditions

thimerosal (ethylmercury) and vaccines

organic mercury, historically used as a preservative, now only used in some multi-dose influenza vaccines

no evidence of association w autism or neurodevelopmental disorders

t/f ethylmercury and methylmercury are the same

false- ethyl has shorter half life and less bioaccumulation

methylmercury and fish

main source of organic mercury exposure, CNS risk at high levels

accumulates in food chain

higher levels in large predatory fish

in general population fish is safe and beneficial

in higher risk pts (pregnant and children) limit high mercury fish

what are common sources of arsenic toxicity?

contaminated groundwater

industrial/environmental exposure

what is the mechanism of toxicity of arsenic?

metalloid (not a true heavy metal)

inhibits pyruvate dehydrogenase

impairs ATP production

acute: severe GI distress, hypotension

chronic: peripheral neuropathy, skin changes (hyperpigmentation)

clues for toxicity- garlic odor, mees lines

chelation therapy

binds metal ions, forms complexes, and increases excretion in urine

used in arsenic, lead, mercury toxicity

what are advantages of chelation therapy?

removes toxic metals, can reduce body burden and prevent progression, life-saving in severe poisoning

what are disadvantages of chelation therapy?

can bind essential metals, side effects, may redistribute metals (transient increase in toxicity), requires monitoring and repeated dosing, not effect for all forms

*tldr toxic gases/asphyxiants

carbon monoxide- interferes w O2 delivery

cyanide- interferes w O2 utilization

what are sources of CO poisoning?

gas powered generators, charcoal grills, propane stoves, charcoal briquettes for cooking and heating, motor vehicles

what is the toxicology of CO?

increase in carboxyHgb

higher affinity for Hgb than O2

impaired O2 delivery

headaches, CNS, and cardiac lesions

what are sources of cyanide toxicity?

smoke inhalation (fires), industrial exposure

what is the mechanism of toxicity of cyanide?

inhibits cytochrome c oxidase

blocks cellular respiration and cells cannot use oxygen

what are key effects of cyanide toxicity?

rapid onset- headache, confusion

severe lactic acidosis

cardiovascular collapse

normal O2 delivery but tissue hypoxia

how can cyanide toxicity be managed?

hydroxocobalamin- binds cyanide → vit B12

± thiosulfate

how does the EPA regulate pesticides?

safety testing includes toxicity, carcinogencity, and reproductive effects

exposure- occupational is highest risk, environmental

toxicity of pesticides depends on…

mechanism and exposure level

what are the major classes of pesticides?

organophosphates- cholinesterase inhibitors

carbamates- reversible cholinersterase inhibition

organochorines (DDT)- persistent environmental toxins

what are sources of organophosphate toxicity?

insecticides, agricultural exposure

what is the mechanism of toxicity of organophosphates?

irreversible acetylcholinesterase inhibition

ACh excess at muscarinic and nicotinic receptors leading to cholinergic crisis

aging causes the enzyme to become permanently inactivated

what are the clinical effects of organophosphate toxicity?

muscarinic- salivation, lacrimation, urination, diarrhea

nicotinic- muscle fasiculations, weakness

CNS- confusion, seizures

how can organophosphate toxicity be managed?

atropine- blocks muscarinic effects

pralidoxime (2PAM)- restores enzymes if used early

supportive care

DDT

environmental toxicant, organochlorine insecticide

what is the mechanism of toxicity of DDT?

alters voltage gated Na+ channels, increases neuronal excitability

highly persistent and bioaccumulates in the food chain

what is an example of DDT toxicity?

eggshell thinning in birds- as a result banned/restricted in many countries

roundup

widely used herbicide- found in agricultural produces

inhibits plant enzyme pathways, low direct toxicity in humans

what is the toxicity of herbicides like glyphosate aka roundup?

irritation at high exposure, no clear evidence of major acute toxicity at typical exposure

not all pesticides are highly toxic to humans

what are common air pollutants and common sources?

particulate matter, ozone (O3), nitrogen dioxide

vehicle emissions, industrial pollution, combustion (indoor/outdoor)

what are mechanisms of toxicity and clinical effects of air pollutants?

oxidative stress, airway inflammation, impaired lung function

cough, wheezing, shortness of breath, exacerbation of asthma/COPD, cardiovascular risk w chronic exposure

what is the dental relevance of air pollutants?

oral inflammation and possible periodontal impact, increased risk in vulnerable patients

key antidote for lead, arsenic, and mercury

chelating agents

key antidote for carbon monoxide

100% oxygen

key antidote for cyanide

hydroxocobalamin

key antidote for organophosphates

atropine and pralidoxime

key antidote for opioids

naloxone

key antidote for benzos

flumazenil

key antidote for acetaminophen

n-acetylcysteine (NAC)

key antidote for warfarin

vitamin K

antidotes target…

the underlying mechanism of toxicity

what are the acute and chronic effects of nitrous?

acute- nausea and dizziness

chronic- vit B12 inactivation leading to megaloblastic anemia and peripheral neuropathy

what are consequences of adverse drug interactions?

decreased therapeutic effect

increased toxicity

unexpected effects

may require hospitalization

what are sources of info for drug interactions?

FDA medwatch, package inserts, clinical databases like lexicom/micromedex, clinical literature and case reports

how are drug interactions identified?

pharmacokinetics and pharmacodynamics

clinical reports and FDA surveillance

clinical trials and post-marketing data

mechanistic research

pharmacokinetic drug interactions

changes in drug concentration, absorption, distribution, metabolism, and excretion

pharmacodynamic drug interactions

changes in drug effect at site of action

what are the types of drug interactions?

additive, synergistic, anatagonistic, unexpected

absorption interactions

often reduce drug effectiveness

drug binding / chelation- decreases absorption of one or both drugs

changes in gastric pH- PPIs, H2 blockers increase gastric pH whihc can decrease the solubility/absorption of some drugs

altered GI motility- opioids decrease gastric emptying and can delay or reduce drug absorption

intestinal transporters and enzymes- CYP3A4 and p-glycoprotein in gut wall can decrease bioavailability of some drugs

why is st john’s wort important?

induces CYP3A4 and Pgp

decreases levels of many drugs like oral contraceptives and antivirals

distribution interactions

displacement from plasma protein binding sites

happens with NSAIDs and warfarin

important for drugs with high proteins binding and narrow therapeutic index

renal clearance interactions

competition for renal transporters (proximal tubules)

organic anion and cation transporters move drugs into urine

competition leads to decreased renal secretion, decreased elimination, and increased drug levels

tldr renal clearance interactions

decreased clearance, increased plasma concentration, increased risk of toxicity