Phar424: Toxicology Part I

Explain the toxicity mechanisms of lead poisoning

-lead affects heme synthesis which results in anemia (low RBC count) -shortens erythrocyte life -affects actively dividing cells -affects morphology of neurons -interferes with neurotransmitter functions -disrupts Ca2+ metabolism

Describe the mechanism of toxicity of carbon monoxide (CO)

1. CO binds to hemoglobin>carboxyhemoglobin, which reduces oxygen (O2) transport 2. carboxyhemoglobin interferes with the release of O2 from oxyhemoglobin Net effect: reduced tissue O2 availability

What is the treatment for carbon monoxide poisoning?

1. CPR 2. Hyperbaric O2

Name 5 toxic Environmental/Air Pollutants discussed in lecture

1. Carbon Monoxide (CO) 2. Persistent organic pollutants (POPs) >Dioxins --polychlorinated dibenzo-p-dioxins=PCDDs --was present in 'agent orange' (DCPA=dimethyl tetrachloroterephthalate) 3. Sulfur dioxide (SO2) 4. Oxides of Nitrogen (NO, N20, NO2) --NO2 in brown colored smog 5. Asbestos 6. Ozone

What are the toxicity manifestations of Lead poisoning? Describe 6 manifestations

1. encephalopathy (acute, emergency) 2. anemia 3. CNS deficits 4. peripheral neuropathy 5. nephropathy 6. hypertension

Lead (Plumbum, Pb) What are three routes of exposure to Lead (Plumbum, Pb)

1. gastrointestinal tract (GI tract)--ingestion 2. respiratory tract--inhalation 3. skin

Describe the symptoms of carbon monoxide poisoning

1. headache 2. dizziness 3. vomiting 4. chest pain

Which of the following federal agencies sets the exposure guidelines for environmental pollutants? A. EPA B. FDA C. FEMA D. OSHA

A. EPA

Describe the toxicokinetics of mercury toxicity (absorption, distribution, metabolism, and excretion)

Absorption: absorbed from respiratory tract, GI tract, and organic form from skin Distribution: mainly to kidney and brain Metabolized: metabolized to divalent mercury Excretion: >inorganic mercury: excreted in urine and feces >alkyl mercury: excreted in feces

Mutagenicity: The ______ test is a widely employed method that uses bacteria to test whether a given chemical can cause mutations in the DNA of the test organism. More formally, it is a biological assay to assess the mutagenic potential of chemical compounds

Ames Test >salmonella typhimurium The Ames test uses several strains of the bacterium Salmonella typhimurium that carry mutations in genes involved in histidine synthesis. These strains are auxotrophic mutants, i.e. they require histidine for growth, but cannot produce it. The method tests the capability of the tested substance in creating mutations that result in a reversion back to a "prototrophic" state, so that the cells can grow on a histidine-free medium

A 1 kg sample of corn flour was found to contain 1 microgram of mercury by the FDA. Which of the following is the MOST accurate way of expressing the amount of mercury present in this sample? A. 0.1 ppm B. 1 ppb C. 0.1 ppb D. 10 ppm

B. 1 ppb (1 x 10^-6 grams) / 1000 grams = 1.0 x 10^-9 = 1 ppb (or 1 x 10^-9)

Which of the following is TRUE regarding indicators of drug safety? A. a drug with a relatively high therapeutic index (TI) usually has a narrow therapeutic window B. A drug with a TI of 10 is relatively safer than a drug with a TI of 2 C. Rodents (e.g. rats, mice) are better predictors of human toxicity compared to dogs D. B and C are true

B. A drug with a TI of 10 is relatively safer than a drug with a TI of 2

Which of the following federal agencies is responsible for protecting the public health by assuring the safety, efficacy and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and products that emit radiation? A. EPA B. FDA C. FEMA D. OSHA

B. FDA

Which of the following types of chemicals are more readily excreted in humans? A. lipophilic chemicals B. hydrophilic chemicals

B. hydrophilic chemicals

Bioactivation: Acetaminophen (see image) Which of the following is the MAJOR type of toxicity produced by an acetaminophen overdose? A. cardiotoxicity B. nephrotoxicity C. hepatotoxicity D. neurotoxicity

C. hepatotoxicity

According to lecture materials, which types of Phase II metabolism reactions may decrease the water solubility of certain xenobiotics? Choose all that apply A. glucuronidation B. sulfation C. methylation D. acetylation

C. methylation D. acetylation

In toxicology, when a non-toxic compound enhances the toxicity of a toxic compound, the effect is known as: A. additive effect B. synergism C. potentiation D. antagonism

C. potentiation

Antidotes for Lead Toxicity: ______therapy is a mainstream treatment used to treat poisoning from toxic levels of certain metals such as lead (Pb) Injections of ________ or other chemicals bind, or chelate, iron, lead, mercury, cadmium, zinc, and some other metals, which are then eliminated from the body.

Chelation therapy (administered I.V.); ethylene diamine tetraacetic acid (EDTA) -mainly used in lead encephalopathy -metal=electron acceptor -chelating agents=electron donors >Form coordinate bonds: >>CaNa2EDTA >>D-Penicillamine (CUPRIMINE) >>Dimercaprol (BAL) >>Succimer (CHEMET) Note: Lead gets bound to EDTA by forming coordinate covalent bonds (chelation). Lead-EDTA complex is then excreted in urine

Which of the following federal agencies requires employers to provide their employees with working conditions that are free of known dangers (i.e. from hazardous waste)? A. EPA B. FDA C. FEMA D. OSHA

D. OSHA (occupational safety and health administration)

The ___________ is the fundamental concept in toxicology that describes the quantitative relationship between the amount of exposure (dose) to a toxicant and the incidence of adverse affects (response)

Dose Response Curve

LD50 and Measures of Toxicity: _______ measures the effective dose in 50% of the population

ED50

Toxicodynamics: Effects of Poison on Body What is dose? -Dose of a chemical or physical agent is the amount of agent that comes into contact with a living organism or part of the living organism.

Exposure dose=the amount of xenobiotic encountered in the environment Absorbed dose: the actual amount of the exposed dose that enters the body Administered dose: the quantity administered orally or by injection Total Dose=the sum of all individual doses

Iron (Fe): Major source: iron supplements, that usually contain ferrous sulfate, FE gluconate, or Fe fumarate. Which one causes more GI irritation?

Fe sulfate (iron sulfate)

Toxicokinetics of Lead (Pb): -absorbed from ____, _____, and _____

GI tract, skin, and lungs

What is the route of administration of carbon monoxide (CO) exposure

Inhalation

The ______is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans; ethical treatment and full consent for studies

Institutional Review Board (IRB)

Dose Response Curve: The ________ is the dose that is lethal in 50% of the exposed animals--is a measure of acute toxicity

LD50

Biomagnification of Mercury: ___________ is methylmercury (MeHg) poisoning that occurred in humans who ingested fish and shellfish contaminated by MeHg discharged in waste water from a chemical plant (Chisso Co. Ltd.). It was in May 1956, that M. d. was first officially "discovered" in Minamata City, south-west region of Japan's Kyushu Island. The marine products in Minamata Bay displayed high levels of Hg contamination (5.61 to 35.7 ppm). The Hg content in hair of patients, their family and inhabitants of the Shiranui Sea coastline were also detected at high levels of Hg (max. 705 ppm). Typical symptoms of M. d. are as follows: sensory disturbances (glove and stocking type), ataxia, dysarthria, constriction of the visual field, auditory disturbances and tremor were also seen. Further, the fetus was poisoned by MeHg when their mothers ingested contaminated marine life (named congenital M. d.). The symptom of patients were serious, and extensive lesions of the brain were observed. While the number of grave cases with acute M. d. in the initial stage was decreasing, the numbers of chronic M. d. patients who manifested symptoms gradually over an extended period of time was on the increase. For the past 36 years, of the 2252 patients who have been officially recognized as having M. d., 1043 have died

Minamata disease

Treatment of Dioxin toxicity: _______ is a fat substitute that has been shown to enhance fecal excretion of dioxins

Olestra (OLEAN)

Preclinical Studies: (see image)

Over 50% of preclinical (before tested on humans) studies occurs using Mice

Biomagnification in Great Lakes: (see image on back)

PCB=Polychlorobiphenyls Concerns about the toxicity of PCBs are largely based on compounds within this group that share a structural similarity and toxic mode of action with dioxin. Toxic effects such as endocrine disruption and neurotoxicity are also associated with other compounds within the group. The maximum allowable contaminant level in drinking water in the United States is set at zero, but due to water treatment technologies, a level of 0.5 parts per billion is the de facto level

Based on the therapeutic indexes of warfarin and penicillin on the previous slides, which one has the larger therapeutic index (ratio of toxic dose in 50% of patients to the effective dose in 50% of patients?)

Penicillin has the larger therapeutic index compared to warfarin

Clinical Studies: Which phase of clinical studies determines the effect of the drug under investigation in HEALTHY volunteer human subjects (50-100); determines toxicity and dose, pharmacokinetics

Phase I

Clinical Studies: Which phase of clinical studies determines the effectiveness of drugs in human subjects for a particular indication (well controlled, monitored, small studies in patients (several hundred patients))?

Phase II

Clinical Studies: Which phase of clinical studies is a double-blind study that compares the effect of the drug under investigation against standard treatment, extrapolation to general population for risk benefit analysis, and information for physician labeling? (several hundred to several thousand subjects are involved)

Phase III

Clinical Studies: What phase of clinical studies does Post-marketing surveillance occur?

Phase IV

Modulation of Toxicity: ___________ occurs if one of the compounds is not toxic by itself, but enhances the toxicity of another compound (2-propranolol and CCl4)

Potentiation (0+1=3)

What is toxicology? "Toxicology is the study of the adverse effects of chemical, physical, or biological agents on living organisms and the ecosystem, including the prevention and amelioration(the act of making something better; improvement) of such adverse effects"-Society of Toxicology

Specialized areas of Toxicology: -Descriptive toxicology -Mechanistic toxicology -Specialized areas >regulatory >forensic toxicology >clinical toxicology >environmental >occupational >analytical

Modulation of Toxicity: _______ occurs if two compounds together cause an effect that is STRONGER than the additive effect of the two (i.e. ethanol and CCl4)

Synergism (1+1=5)

LD50 and Measures of Toxicity: _______ measures the toxic dose in 50% of the population

TD50

Topical/Ocular Toxicity Testing: -Rabbits (commonly an albino rabbit) The ______ Test is an acute toxicity test, initially used for testing cosmetics, the procedure involves applying 0.5mL or 0.5g of a test substance to the eye or skin of a restrained, conscious animal, and then leaving it for set amount of time before rinsing it out and recording its effects

The Draize Test >skin-applied to shaved skin >eye-instilled in the eye -The animals are observed for up to 14 days for signs of erythema and edema in the skin test, and redness, swelling, discharge, ulceration, hemorrhaging, cloudiness, or blindness in the tested eye. The test subject is commonly an albino rabbit, though other species are used too, including dogs Alternative tests: -epidermal keratinocyte culture -corneal epithelial culture

How do you calculate Therapeutic index in human?

Therapeutic index (TI) = Toxic dose in 50% of patients (TD50) / Effective dose in 50% of patients (ED50) Note: In animal studies, TI=LD50/ED50 >LD50 is lethal dose, TD50 is toxic dose, ED50 is effective dose

Toxicity Assessment in Animals and Humans: Acute toxicity: -LD50 (lethal dose) determination -usually rodents -OECD 25 guidelines (Up and Down procedure) >>software predicts maximum likely hood for a median 50% lethal dose

Up-and-down procedure (or method) is an alternative to the LD50 acute toxicity test It requires fewer animals to achieve similar accuracy as the LD50 test. However, the U.S. Food and Drug Administration has begun to approve non-animal alternatives

Duration of Exposure: ___exposure = less than 24 hours of exposure

acute

Modulation of Toxicity: The ________ occurs if two compounds that causes similar types of toxicity cause an effect that is the sum of the individual effects (i.e. toluene and p-xylene)

additive effect (1+1=2)

Modulation of Toxicity: __________ occurs if one of the compounds is not toxic by itself, but DECREASES the toxicity of another compound

antagonism (1+0=0)

Toxicokinetics of Lead (Pb): Lead (Pb) binds to _______ and is distributed mainly to ____, ____ , and _____

binds to erythrocytes; distributed mainly to brain, kidney, and liver

_________ is the accumulation of a substance, such as a toxic chemical, in various tissues of a living organism. _____(same as previous) takes place within an organism when the rate of intake of a substance is greater than the rate of excretion or metabolic transformation of that substance

bioaccumulation

_________ is the metabolic activation of xenobiotic compounds into reactive, toxic compounds

bioactivation

_________ is the increasing concentration of a substance, such as a toxic chemical, in the tissues of organisms at successively higher levels in a food chain

biomagnification

Toxicokinetics of Lead (Pb): Lead (Pb) is deposited in _____ and ____ for years

bone and teeth

Duration of Exposure: ______ exposure = greater than 3 months of exposure

chronic

_________ is the physiological or medicinal removal of toxic substances from the body

detoxification

What drug is usually given to control seizures associated with carbon monoxide poisoning?

diazepam

__________ is the state of being exposed to or in contact with something (acute, chronic, repeated)

exposure

_____ is the ability of a toxic agent to cause injury in a given situation or setting

hazard

Dose Response Curve: What does the NOAEL tell on the dose response curve?

highest dose at which no adverse effects are observed

_________ is an abnormal state that is essentially a poisoning

intoxication

Mercury Toxicity (Hg): Describe the toxicity mechanisms and effects of mercury poisoning

largely unknown; 1. interacts with SH groups in enzymes 2. causes necrosis of proximal tubule epithelium Toxic effects: 1. acute inhalation of mercury vapors may cause chemical pneumonitis and noncardiogenic pulmonary edema 2. chronic inhalation of mercury vapor results in a classic triad of tremor, neuropsychiatric disturbance, and gingivostomatitis. 3. organic mercury is more toxic to CNS

Dose Response Curve: What does the LOAEL tell on the dose response curve?

lowest dose at which adverse effects (toxicity) are observed

________ are toxicants that cause immediate death or illness when experienced in very small amounts

poisons

Duration of Exposure: ____ exposure= up to 1 month of exposure

subacute

Subacute and Subchronic toxicity Testing: To test for _______ toxicity, xenobiotic is usually administered for 14 days, and the aim is to determine doses for subchronic study

subacute toxicity

Duration of Exposure: _____exposure= 1-3 months of exposure

subchronic

Subacute and Subchronic toxicity To test for _____ toxicity, xenobiotic is usually administered for 90 days, conducted in 2 species, and at least 3 doses are used

subchronic toxicity

__________the range of dosage of a drug or of its concentration in a bodily system that provides safe effective therapy

therapeutic window

Dose Response Curve: The __________ is the MINIMUM dose at which toxicity occurs

threshold

_______ are substances that produce adverse biological effects of any nature

toxicants

______ are specific proteins created by plants and animals that are poisonous to humans

toxins

Toxicokinetics of Lead (Pb): Lead (Pb) is mainly excreted through _____

urine

A _______ is a foreign chemical substance found within an organism that is not normally naturally produced by or expected to be present within that organism

xenobiotic