DABAT cheat sheet

Dose-response: graded responses describe an individual's intensity of effect versus dose; quantal responses describe the proportion of a population responding, yielding ED50, TD50, and LD50 values.

Therapeutic index = TD50/ED50; a larger value indicates a wider margin of safety. Certain safety factor = LD1/ED99, which is more conservative than the therapeutic index.

Threshold dose-response assumes a dose below which no adverse effect occurs; non-threshold models (linear, no-threshold) are applied to genotoxic carcinogens and radiation for regulatory purposes.

Hormesis is a biphasic dose-response with low-dose stimulation or benefit and high-dose inhibition or toxicity; it is descriptive and does not by itself establish a safe threshold.

LD50 is a statistically derived single-dose estimate that varies with species, strain, route, vehicle, and observation period; it does not describe slope, reversibility, or mechanism.

Exposure is quantified as dose = (concentration × intake rate × exposure duration)/body weight; inhalation dose uses minute ventilation and retention fraction rather than intake rate.

Xenobiotic disposition proceeds through absorption, distribution, metabolism (functionalization then conjugation), and excretion; toxicokinetics describes how these processes alter the toxicant concentration at the target site.

Toxicodynamics covers toxicant-receptor interaction, signal transduction, and cellular repair or compensation; the same dose can produce different effects depending on target-site sensitivity and repair capacity.

First-order elimination: rate is proportional to concentration, half-life is constant, and about 4-5 half-lives are required to reach steady state or near-complete elimination.

Zero-order (saturation) elimination: a constant amount is removed per unit time, so half-life lengthens as concentration rises; classic examples are ethanol, phenytoin at high concentrations, and high-dose salicylate.

Volume of distribution Vd = amount in body/concentration in plasma; a large Vd (>1 L/kg) indicates extensive tissue distribution and limits usefulness of hemodialysis.

Clearance CL = elimination rate/plasma concentration, and half-life t1/2 = 0.693 × Vd/CL; changing Vd or CL independently alters half-life.

Bioavailability F = (AUC oral × dose IV)/(AUC IV × dose oral); first-pass hepatic metabolism reduces F and can be saturated, causing disproportionate rises in exposure.

The two-compartment model shows a rapid distribution phase (alpha) followed by a slower elimination phase (beta); post-distribution sampling is required for reliable kinetic estimates.

Michaelis-Menten kinetics: rate = (Vmax × C)/(Km + C); at C much greater than Km the process is zero-order, and at C much less than Km it is effectively first-order.

Toxicokinetic interactions include enzyme induction (e.g., CYP1A2, CYP2E1, CYP3A4) and inhibition, protein-binding displacement, competition for renal tubular secretion, and enterohepatic recirculation prolonging exposure.

Covalent binding of reactive metabolites to macromolecules is a common initiation step; acetaminophen's NAPQI binding to hepatic proteins is the prototypical example.

Oxidative stress arises when reactive oxygen species exceed antioxidant defenses (glutathione, superoxide dismutase, catalase, glutathione peroxidase), causing lipid peroxidation and protein oxidation.

Glutathione depletion is a shared mechanism of hepatotoxicity for acetaminophen, methionine, and other electrophiles; N-acetylcysteine replenishes cysteine for glutathione synthesis.

Mitochondrial toxicity mechanisms include uncoupling of oxidative phosphorylation (e.g., dinitrophenol), inhibition of the electron transport chain (e.g., cyanide at complex IV), and opening of the mitochondrial permeability transition pore.

Enzyme inhibition explains many acute poisonings: organophosphates inhibit acetylcholinesterase, carbon monoxide binds hemoglobin, and fluoroacetate blocks aconitase via fluorocitrate.

Receptor-mediated toxicity includes nicotinic and muscarinic cholinergic excess, GABA-A antagonism (e.g., convulsants), and opioid mu-receptor agonism with respiratory depression.

Hypersensitivity and idiosyncratic reactions are not predicted by dose-response and may involve hapten formation, HLA-associated immune responses, or metabolic polymorphisms.

Carcinogenesis mechanisms include genotoxicity (DNA adducts, strand breaks, mutations) and non-genotoxic mechanisms (cytotoxicity with compensatory proliferation, hormonal disruption, epigenetic alteration).

The four-step risk assessment paradigm: hazard identification, dose-response assessment, exposure assessment, and risk characterization.

Reference dose (RfD) = NOAEL or benchmark dose divided by uncertainty factors; typical defaults are 10 for interspecies, 10 for intraspecies, and additional factors for database deficiency or severe effects.

Cancer slope factor converts lifetime average daily dose to incremental cancer risk: risk = slope factor × average daily dose; slope factors derive from the linearized multistage or benchmark dose models.

Margin of exposure (MOE) = point of departure/exposure; for genotoxic carcinogens, MOEs of 10,000 or more are generally considered low concern, with lower thresholds for non-genotoxic effects.

Acceptable daily intake and tolerable upper intake levels are health-based guidance values; they are not regulatory limits, which also incorporate feasibility and analytical capability.

Occupational exposure limits differ in legal status: OSHA PELs are enforceable, whereas NIOSH RELs and ACGIH TLVs are recommendations or guidance.

Biomonitoring equivalents and biological exposure indices translate external exposure into internal dose markers measured in blood, urine, or exhaled air.

Regulatory frameworks include TSCA, FIFRA, the Clean Air and Clean Water Acts, REACH, and GHS hazard communication; each has distinct data requirements and risk-management provisions.

Toxidrome recognition: cholinergic (DUMBELS plus bronchorrhea), anticholinergic (dry skin, mydriasis, delirium, urinary retention), sympathomimetic, opioid, sedative-hypnotic, and serotonergic syndromes each have characteristic vital-sign and pupil patterns.

Anion gap = Na - (Cl + HCO3); normal is roughly 8-12 mEq/L. A high anion gap acidosis suggests methanol, ethylene glycol, salicylate, lactate, uremia, or ketoacidosis.

Osmolal gap = measured osmolality - calculated osmolality (2Na + glucose/18 + BUN/2.8); it is useful early in toxic alcohol ingestion before metabolism generates acid.

The delta-delta ratio (delta anion gap/delta bicarbonate) helps distinguish pure high-anion-gap acidosis from mixed disorders and from superimposed metabolic alkalosis.

Carboxyhemoglobin and methemoglobin are measured by co-oximetry, not standard pulse oximetry; standard SpO2 can be normal despite severe carbon monoxide or methemoglobinemia.

Acetaminophen concentration should be measured in every intentional overdose and interpreted with the Rumack-Matthew nomogram using time since ingestion and treatment with N-acetylcysteine.

The electrocardiogram guides risk stratification: QRS widening suggests sodium channel blockade, QT prolongation suggests potassium channel blockade, and bradycardia with hypotension suggests digoxin toxicity.

History should establish agent, dose, route, timing, co-ingestants, symptoms, and medical and psychiatric history; pill identification, prescription monitoring, and collateral sources supplement an unreliable history.

Activated charcoal is most effective within one hour of ingestion and is contraindicated or relatively contraindicated with unprotected airway, gastrointestinal obstruction, and caustic or hydrocarbon ingestion.

Whole-bowel irrigation with polyethylene glycol is considered for sustained-release products, iron, lithium, and body packers; it is contraindicated with ileus, obstruction, or hemodynamic instability.

Antidote pairings: naloxone for opioids, N-acetylcysteine for acetaminophen, fomepizole or ethanol for methanol and ethylene glycol, sodium bicarbonate for salicylate and sodium-channel blockade, and calcium salts for hydrofluoric acid and calcium channel blocker toxicity.

Additional antidotes: glucagon and high-dose insulin-euglycemia for beta-blocker toxicity, lipid emulsion for local anesthetic systemic toxicity, hydroxocobalamin for cyanide, and octreotide for sulfonylurea-induced hypoglycemia.

Hemodialysis removes low-molecular-weight, water-soluble, low-Vd, low-protein-bound toxins such as methanol, ethylene glycol, lithium, salicylate, and theophylline.

Urinary alkalinization with sodium bicarbonate enhances salicylate and phenobarbital elimination by trapping the ionized form in urine.

Multiple-dose activated charcoal enhances elimination of drugs undergoing enterohepatic recirculation or with a long half-life, such as carbamazepine, theophylline, phenobarbital, and dapsone.

Gastric lavage and induced emesis are rarely indicated; ipecac is no longer recommended for routine poisoning management because of lack of benefit and risk of aspiration.

Ethanol withdrawal: tremor, diaphoresis, tachycardia, and anxiety begin 6-24 hours after the last drink; seizures occur at 12-48 hours and delirium tremens at 48-96 hours. Benzodiazepines are first-line treatment.

Opioid withdrawal produces yawning, lacrimation, rhinorrhea, piloerection, diarrhea, and mydriasis; it is rarely fatal, and buprenorphine or methadone treats it.

Benzodiazepine withdrawal can cause seizures and delirium and is potentially fatal; it requires a gradual taper rather than abrupt discontinuation.

Opioid overdose presents with miosis, respiratory depression, and depressed mental status; naloxone reverses it, but repeated dosing may be needed for long-acting or high-potency opioids.

Sympathomimetic toxicity from cocaine or amphetamines causes hypertension, tachycardia, hyperthermia, and agitation; benzodiazepines are first-line, and sodium bicarbonate is used for QRS widening.

Alcohol biomarkers include ethyl glucuronide and ethyl sulfate in urine, phosphatidylethanol in blood, and carbohydrate-deficient transferrin; each has a different detection window.

Neonatal abstinence syndrome follows in-utero opioid exposure and presents with irritability, tremor, feeding difficulty, and autonomic instability; it is scored and treated with opioid taper.

Substance use disorder is defined by DSM-5 criteria spanning impaired control, social impairment, risky use, and pharmacological criteria such as tolerance and withdrawal.

Lead exposure causes anemia from heme synthesis inhibition (increased protoporphyrin, basophilic stippling), hypertension, peripheral neuropathy, and cognitive effects; blood lead and zinc protoporphyrin are used for monitoring.

Mercury toxicity varies by form: elemental vapor causes tremor and erethism, inorganic salts cause renal tubular injury, and methylmercury causes paresthesias and ataxia.

Organophosphate and carbamate insecticides inhibit acetylcholinesterase; atropine treats muscarinic effects, and pralidoxime reactivates phosphorylated enzyme if given before aging.

Carbon monoxide binds hemoglobin with high affinity, shifting the oxygen dissociation curve leftward; treatment is high-flow oxygen, and hyperbaric oxygen is considered for severe poisoning.

Hydrogen sulfide and cyanide both inhibit cytochrome c oxidase; hydrogen sulfide also causes olfactory fatigue, so absence of odor does not exclude dangerous exposure.

Asbestos exposure causes asbestosis, mesothelioma, and lung cancer; latency is long, and smoking synergistically increases lung cancer risk.

Benzene is a recognized leukemogen associated with acute myeloid leukemia; toluene and xylene primarily cause central nervous system depression.

Airborne exposure assessment uses personal sampling in the breathing zone, expressed as time-weighted average over a shift, with short-term exposure limits for peaks.