Safety Engineering

-Toxicology-

• Denotes the probability of injury or illness from contact or use

• Industrial Hazards

– Explosivity

– Ignitability

– Reactivity

– Toxicity

Hazardous 2

• Capacity of a substance to produce injury or illness

• Acute Effects

– Short term, appear shortly after exposure. Can be from single exposure

• Chronic Effects

– There is a latency, long period of time before you see effect

Toxic Substance 3

• Chemical Agents (poisons)

• Physical Agents (dusts under 5 m, fibers)

• Biological Agents (pathogens)

Toxic Hazardous Materials 4

• Toxicology is the quantitative and qualitative study of the adverse effects of toxicants on biological organisms.

• Toxicant is a chemical or physical agent that produces adverse effects on biological organisms.

• Poison is a toxicant that cause immediate death or illness when experienced in very small amounts.

Definitions

• How toxicants enter the organism

• How toxicants effect the organism

• How toxicants are eliminated from (leave) the organism

All substances are toxic if taken in the wrong quantities.

Toxic Hazardous Materials 5

So Toxicology is the study of:

• Inhalation (mouth or nose to lungs) then into blood(+*)

• Ingestion (mouth to stomach) then into blood(+)

• Injection (cuts, punctures in skin) into blood

• Dermal absorption (through skin) into blood(+*)

+ Involve membrane transport

* Greatest threats in industry

How toxicants enter organism 6

Routes of Exposure 7

Inhalation (lungs) Most important route if exposed to gases, vapors, mists, aerosols.

– Influenced by respiration rate, concentration, duration.

Key factors for gases and vapors:

• solubility and reactivity

Key factors for aerosols:

• particle size and solubility respirable size: 0.1 m to 10 m

• < 5 m reach alveolar region

Certain Effects of Chemicals on the Lungs

• Irritations – acid mists (HCl)

• Edema – phosgene (COCl2)

• Emphysema – smoke (esp. tobacco)

• Fibrosis – silicon dioxide (SiO2)

• Cancer – asbestos (mesothelioma)

Routes of Exposure 8

Skin absorption

• Depends on site of contact

temperature (vasodilatation)

thickness, blood flow

• Depends on skin condition

integrity; pH

• Time-dependent (duration)

• Properties of the toxin

concentration

reactivity

solubility (in fat/water)

molecular size

Routes of Exposure 9

Ingestion (mouth)

Rare, but contamination can = intake

mucociliary action of respiratory tract

• Stomach Gastrointestinal tract bloodstream

• Absorbed - systemic injury

• Liver, kidney; Detoxification process

Inflammation

cirrhosis - fibrotic liver disease

malignant tumors

• Factors: physical state, duration

Routes of Exposure 10

Injection

Directly into bloodstream “sharps”, needles, broken glassware

skin puncture or injuries

• Bypasses protective mechanisms

• Usually rare in workplace primarily associated with bloodborne pathogens

(biomedical facilitates)

especially hazardous in health care industry

• Carcinogen - causes cancer

• Mutagen - causes chromosome damage

• Reproductive hazard - damage to reproductive system

• Teratogen - causes birth defects

Effects of Toxicants 11

Irreversible Effects

May or may not be reversible

• Dermatotoxic – affects skin

• Hemotoxic – affects blood

• Hepatotoxic – affects liver

• Nephrotoxic – affects kidneys

• Neurotoxic – affects nervous system

• Pulmonotoxic – affects lungs

• Excretion through kidneys, liver and lungs

• Detoxification is the biotransformation of chemicals into something less harmful

• Storage in fatty tissue

Elimination of toxins 12

• Determine toxic effect – local effect, target organ, systemic effect, acute, chronic effects.

• Determine toxic dose – identify the dose that will produce a given toxic effect.

Toxicity Studies 13

Difficulties in Toxicological studies

No ethical way to get human volunteers, hence need to use “model” systems of rats, cats, dogs, rabbits, etc. High doses in animals are needed to predict possible hazard to

humans Specificity of individual response

• Allergy or immunity • Statistical study required • Organism specific response, not applicable to humans • Dosage response • Response time, latency, acute versus chronic • Difficulty in measuring intended variable (lead in liver measured

by lead in blood)

• Run test on “large” population

• Given same dose (usually in dose/body mass)

• Determine the number or fraction of individuals

that have a response

Dose-Response Relationship 14

Basic Concepts

• Dose and response can be measured. • Response magnitude is related to dose. • All toxic interactions follow a dose-response relationship. • With increasing dose, there is an increase in the number

affected and/or an increase in the intensity of the effect

Dose = (Concentration) x (Time)

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20• Repeat tests using different doses

• Find average response to each dose

• Plot Response versus logarithm of dose

• Forms Sigmoid shaped curve

Dose-Response Relationship 15

This relationship is unique for each chemical

Dose units

• Quantity per unit mass (mg/kg)

• Quantity per unit area of skin surface (mg/m2)

EDf – Effective dose for f percent of population. Reversible response

TDf – Toxic dose for f percent of population. Undesirable response that is irreversible

LDf – Lethal dose for f percent of population.

Dose-Response Terms 16

TDlo – Toxic dose low - lowest dose for effect LD10 – Lethal dose 10% - dose that causes death in 10% of the test population LD50 – Lethal dose 50% - dose that causes death in 50% of the test population TClo – Toxic concentration low - used to express toxic concentration via inhalation LC10 – Lethal concentration 10% - dose that causes death in 10% of the test

population –via inhalation LC50 – Lethal concentration 50% - concentration that causes death in 50% of the

test population via inhalation

Lethal dose 17

Agent LD50 (mg/kg)

Ethyl Alcohol 7060

Sodium Chloride 3000

Naphthalene 1760

Ferrous Sulfate 1500

Aspirin 1000

Formaldehyde 800

Ammonia 350

Dextromethorphan Hydrobromide 350

Caffeine 192

Phenobarbital 150

Chlorpheniramine Maleate 118

DDT 100

Strychnine Sulfate 2

Nicotine 1

Dioxin 0.0001

Botulinus Toxin 0.00001

Toxicity Rating (LD50) Dose for 70 kg person • Super Toxic < 5 mg/kg • Extremely Toxic 5 – 50 mg/kg • Very Toxic 50 – 500 mg/kg • Moderately Toxic 0.5 – 5 g/kg • Slightly Toxic 5 – 15 g/kg • Practically Nontoxic >15 g/kg

Target Organs 18

Organs selectively affected by harmful agent:

– Lungs (pneumotoxicity)

– Blood (hematotoxicity)

– Liver (hepatotoxicity)

– Kidneys (nephrotoxicity)

– Nervous system (neurotoxicity)

– Immune system (immunotoxicity)

– Embryos/fetuses (reproductive & developmental toxicity)

Target Organ Effects 19

Toxins Target organ

Signs &

Symptoms Examples

HEPATOTOXIN LIVER JAUNDICE CCl 4

NEPHROTOXINS KIDNEY EDEMA HALOGENATED

HYDROCARBONS

NEUROTOXINS CNS NARCOSIS BEHAVIOR MERCURY

HEMATOPOIETIC SYSTEM HEMOGLOBIN CYANOSIS CO, CS 2

LUNG AGENTS PULMONARY TISSUE COUGH,CHEST

TIGHTNESS SILICA, ASBESTOS

REPRODUCTION TOXIN

REPRODUCTIVE SYSTEM BIRTH DEFECTS LEAD

CUTANEOUS AGENTS SKIN RASHES; IRRITAION KETONE

EYE HAZARDS EYES CONJUCTIVITIS ORGANIC SOLVENTS

Exists in elemental form and in the tri- and pentavalent oxidation states, copper mining & smelting

Toxicity rating: RAs –X < As+5 < As+3 < AsH3

Absorption, distribution and excretion

Variable absorption, soluble salts well absorbed and insoluble salts are poorly absorbed

Distribution: liver and kidney, hair and nails

Excretion

a) Excreted in urine

b) Half-life about 2 days

Biochemical mechanism of toxicity

As+5 reacts with thiols, uncouples energy production

As+3 uncouples oxidative phosphorylation

Toxic Effects 20

Arsenic (in detail)

Arsenic poisoning 1. Early signs and symptoms

Diarrhea

Skin pigmentation

Hyperkeratosis

Edema of lower eyelids, face and ankles

Garlic odor of breath

2. Progression Dermatitis and keratosis of palms, soles – skin cancer

Enlarged liver

Renal injury

Peripheral neuropathy (legs more than arms – contrast to lead)

Encephalopathy

Aplastic anemia, lung & skin cancer

Arsine (AsH3)

1. Gas

2. Hemolysis

Toxic Effects 21

Arsenic (cont.)

Acute cadmium poisoning • Oral – gastrointestinal effects

• Inhalation – local irritation of respiratory tract

Chronic cadmium poisoning • Kidney - Most cadmium sensitive organ

• Lungs After inhalation

Emphysema

• Cardiovascular – hypertension

• Bone

• Testes – sensitive after acute, not after chronic

Toxic Effects 22

Cadmium

Metal fume fever, Cd, An, Mg Batteries, welding, coal & fossil fuel burning

Acute lead poisoning • Rare

Chronic inorganic lead poisoning (plumbism) • Gastrointestinal effects

More common among adults

Referred to as lead colic, often symptoms for which patient seeks relief

Organic lead poisoning • CNS: insomnia, nightmares, irritability, anxiety, anemia, kidney

• Car exhaust is organic

Toxic Effects 23

Lead

CNS: Central Nervous System

Paint (old), plumbers, US moonshine, pottery glazing (old), water pipes (old), was in gasoline, Initially in liver & kidneys

Chronic mercury poisoning • CNS effects:

• Mercury vapor (elemental mercury): largely neuropsychiatric: depression, irritability, shyness, insomnia, emotional instability, forgetfulness, confusion, excessive perspiration, uncontrolled blushing (erethism) and tremors

• Methylmercury Paresthesia (abnormal spontaneous sensation, ex. tingling)

Visual changes (constriction of visual field)

Hearing defects

Dysarthria (speech disorder)

Ataxia (unstable gait, coordination, loss of muscle movement)

Fetus is extremely susceptible

• Inorganic mercury: little known

1. Kidney: target organ of inorganic mercury toxicity

a) Organomercurials-high fetal toxicity

Toxic Effects 24

Mercury

Aluminum

Low toxicity, aluminum hydroxide is antacid

Shaver’s disease – by inhalation in industry – lung fibrosis

Antimony: toxicity similar to arsenic, garlic breath

Beryllium

Mining

Berylliosis / granuloma

Chromium

Necessary for glucose metabolism (trivalent)

Insoluble hexavalent cause lung cancer by inhalation

Toxic Effects 25

Other Metals

Cobalt Essential element in vitamin B12

Polycythemia (increase in RBC)

Goiter

Cardiomyopathy – beer drinkers

Copper Essential element

Wilson’s disease (hereditary, retains copper)

Metal fume fever

Fluoride Reduces dental caries at 0.7-1.2 mg/1 or ppm

Dental fluorosis (discoloration and/or pitting) in children above 2 ppm

Brittle bones at higher concentrations

Discolors leaves

Toxic Effects 26

Other Metals

27

Iron, Fe2O3

Metabolic acidosis – cell death through hemosiderin

Manganese Manganese pneumonitis

CNS: Parkinson’s disease

Nickel Dermatitis (nickel itch, jewelers itch)

Nickel carbonyl (Ni[CO]4) – carcinogenic, highly acutely toxic, pneumonitis leukocytosis, temperature, delirium

Nickel subsulfide – carcinogen in humans (nose)

Toxic Effects 27

Other Metals

Phosphorus Used in matches, rat poisons, fireworks

GI upset – vomitus may be phosphorescent

Liver injury – jaundice

Chronic – necrosis of bone “phossy jaw,”

Selenium Essential (glutathione peroxidase)

Excess in livestock – “blind staggers or alkali disease” characterized by lack of vitality, loss of hair, sterility, atrophy of hooves, lameness and anemia

Excess in humans – discolored/decayed teeth, skin eruptions, GI distress, partial loss of hair and nails, garlic breath

Liver injury

Silver Skin – argyria (blue skin)

Toxic Effects 28

Other Metals

GI - gastrointestinal

Thallium Rodenticides, ant poison (discontinued many countries)

Distributed like potassium, mining

GI irritation – acute

Alopecia

Uranium Kidney injury

Zinc Essential

Acute oral toxicity: vomiting, diarrhea, fever

Inhalation: metal fume fever - fever

Toxic Effects 29

Other Metals

• Acute – CNS depression, defatting skin, myocardium

• Chronic – liver, kidney

• Chlorinated – solvents (CNS/skin/cancer)

CCl4 - carcinogenic, liver, kidney

• Brominated – fumigant, solvents (CNS/skin)

• Fluorinated – refrigerants (ozone layer/myocardium)

Toxic Effects 30

Halogenated Hydrocarbons

- low flammability, excellent solvents

• Benzene – CNS depression, leukemia

• Toluene – CNS depression (glue sniffers)

• Styrene – dermatitis, CNS depression

• Poly-aromatic hydrocarbons – doxin, PCBs, biphenyls – liver/thyroid/skin

• Nitrobenzene – CNS, jaundice (liver effect), methemoglobin - blue lips & fingernails

• Phenol – CNS, liver, kidney, skin effects

(absorbed readily through skin)

Toxic Effects 31

Aromatic Hydrocarbons

32

Methanol – alcohol dehydrogenase- blindness-treat with ethanol

Ethanol – CNS depression, fetal alcohol syndrome, liver cirrhosis

Isopropanol – CNS depression, gastritis

Toxic Effects 32

Aliphatic Alcohols

Ethylene glycol monomethyl ether (EGME) CH3OCH2CH2OH Disrupts sperm development

Developmental toxin – day 7,8-neural tube; day 10-11-digit/paw effects, brain, liver, and kidney

Ethylene glycol monoethyl ether (EGEE) CH3CH2OCH2CH2OH Testicular degeneration

Reproductive/developmental toxins, but less severe

Propylene glycol monomethyl ether (PGME) Not a reproductive/developmental toxin

Toxic Effects 33

Glycol Ethers

• Acetone (dimethyl ketone) – CNS, skin effects

• Methyl ethyl ketone – CNS, skin, reproductive and developmental effects

• Methyl butyl ketone – CNS and peripheral nervous system effects

Toxic Effects 34

Ketones

• Organophosphates – cholinesterase inhibitor; parathion, dursban, dichlorvos,

• Organochlorine – CNS; DDT, aldrin, kepone, mirex

• Carbamates – reversible cholinesterase inhibitor; sevin

• Chlorophenoxy – liver, kidney, CNS; 2,4-D, agent orange, 2,4,5-T

• Pyrethrins – CNS effects; resmethrin

Toxic Effects 35

Pesticides