Intro Toxicity Flashcards
How are tests done on animals?
-ingestion, skin application, inhalation, gavage
-placing the product in water or air of test animal’s environment
What does cruelty-free mean?
-there are no laws surrounding the statement
-could mean the final product is not currently being tested on animals, but the separate ingredients probably have been
what are some measures of toxicity?
-mortality
-teratogenicity (causes birth defects)
-carcinogenicity (cause cancer)
-mutagenicity (causes heritable change in DNA)
How is toxicity measured?
-as clinical “endpoints”
What is LD50?
-median lethal dose
-dose where 50% of the population would die
-expressed in mg/kg
What is the definition of poison?
-any pesticide with LD50 of 50mg/kg or less
-must have labels
-must have “danger” and “poison”
-must have skull with crossbones
What are the LD50 of some insecticides?
-nicotine = 50mg/kg
-TCDD (dioxin) = 0.1mg/kg
-parathion = 13 mg/kg
-malathion = 370 mg/kg
What are heavy metals?
-chemical elements with specific gravity less than 5x specific gravity of water
-atomic weight greater than Na and density greater than 5 g/cm^3
-high reflectivity, electrical/thermal conductivity, strength
-usually includes lead, cadmium, mercury
How are metals absorbed through the respiratory system?
-vapor or aerosol
-readily absorbed in alveolar space
-larger particles cleared via mucociliary transport and swallowed
-small particles may reach gas exchange and can be absorbed into blood
how are metals absorbed into the gastrointestinal tract?
-through food or water
-absorbed in GI tract lining via diffusion, transport or pinocytosis
What are some factors that change the absorption of heavy metals in the GI tract?
-metal solubility
-chemical forms of metal (methyl mercury is lipid soluble vs inorganic mercury isn’t)
-similar composition = similar absorption sites (calcium & lead)
-physiological state of the person (ex. vit d increases lead abs.)
Which heavy metals are readily absorbed in alveolar space?
-cadmium
-mercury
-tetraethyl lead
How are heavy metals excreted from the body?
-metals in blood can be bound to plasma proteins and AA
-if bound to low MW proteins and AA = filtered in glomerulus into fluid of renal tubule
-Cd and Zn can be reabsorbed in the tubule
Can enterohepatic circulation occur with heavy metals?
-yes
-absorbed metal may be excreted into bile, pancreatic secretions, or saliva
What are some minor pathways of excretion for heavy metals?
-hair (Hg, Zn, Cu, As)
-nails
-saliva
-perspiration
-exhaled hair
-lactation
-exfoliated skin
What is the acute toxicity of metals?
-pt not usually exposed and suddenly gets exposed to it
-from high-concentration exposure with little opportunity to detoxify, eliminate, or adapt
How is acute toxicity of metals treated?
-increase elimination
-prevent irreversible organ/tissue damage
-treat symptoms
What is the chronic toxicity of metals?
-more problematic because you cannot tell that it’s occurring until it has accumulated over time
-diagnosed by finding excessive metals in blood and urine
-organs not involved in abs or elim of metals may also be affected
What are the similarities and differences between acute and chronic metal toxicity?
Difference: the time between exposure and symptoms is different, organs affected is different
Similarities: treatment and most symptoms
Where can lead be found and lead to exposure?
-outdoor paint products (lead in residential paint banned in 1977)
-soil
-dust
-paint chips
-contaminated water
- lead-related occupation
-folk remedies
-congenital exposure
What are the two lead types still used in some countries?
-tetraethyl lead
-tetramethyl lead
-found in gasoline
What are the kinetics and dynamics of lead in the body?
Abs:
-Lungs: if small enough
-GI: children abs more than adults
-Skin: organic lead well abs
Distribution: bound to RBC, goes to bone, teeth, liver, lung, brain (crosses BBB), placenta, etc.
Excretion:
-kidney: 30ug-200ug/day
-feces
Which type of lead is better absorbed through the skin?
-organic lead is well-absorbed
-inorganic lead is not well absorbed
Acute vs chronic lead toxicity clinical manifestations
-acute tox: causes acute encephalopathy, renal failure, and severe GI symptoms
-chronic tox: lead has an affinity for SH groups and toxic to zinc-dependent enzyme systems
-uses the same channels in the heart as other ions
What are some systems that are affected by chronic metal toxicity?
-heme synth:
-steroid met and membrane integrity
-interferes with vit D synth in renal tubular cells
What Vit D synthesis rxn is affected by chronic metal toxicity?
conversion of 1-hydroxyvitamin D to 1,25-hydroxyvitamin D
What are the two main effects of lead toxicity?
-when lead levels increase in the blood they cross the BBB and cause cellular and neurological effects
What is the pathway for cellular effects from lead toxicity?
-cellular effects -> hormone activates G protein -> opens Ca channel -> ER release of Ca -> lead enters cell via Ca channels -> binds with calmodulin -> inflam, met, apoptosis, muscle contraction, improper immune stimulation
What is the pathway for the neurological effects of lead toxicity?
-neurological effects -> disrupts astrocytes and endothelial -> plasma moves into interstitial space -> increased intracranial pressure -> edema, encephalopathy, irreversible brain damage
What is the MOA of lead?
acts as a substitute to other bivalent cations like Ca2+, Mg2+, Fe2+ and monovalent cations like Na+
Where can mercury be found?
-three forms: elemental, inorganic salts, organic
-mining, smelting and industrial discharges = contamination
-can convert to organic mercury via bacteria in fish
-organic more toxic than inorganic
-found in thermometers, light bulbs, disc batteries
What are the effects of elemental mercury?
-acute necrotizing bronchitis, pneumonitis, death
-long term: early-stage -> insomnia, forgetfulness, anorexia, mild tremor
late-stage -> progressive tumor, erethism, salivation, renal toxicity
-dental amalgams do not pose risk
What are the effects of inorganic mercury?
-GI ulceration and hemorrhage
-breakdown mucosal barriers
-Acrodynoa: pink disease; from dermal exposure; maculopapular rash and swelling
What are the effects of organic mercury?
-CNS effects: paresthesias, weakness, tremor, coma and death
-Tetrogen effects: asymptomatic mothers give to child = retardation, blindness, deafness, seizures
What is the plausible pathway for ethyl mercury toxicity?
-mercury preservative -> ethyl mercury -> goes to brain and decreases glutathione -> neuroinflammation and oxidative stress = increases free radicals -> encephalopathy
Why do bigger fish have more mercury than smaller fish?
-because bigger fish eat all the smaller fish and smaller organisms that contain mercury and the mercury accumulates
-food chain
What are the biological effects of mercury?
-CNS = neuropsychiatric (tremor, insomnia, depression), sensorimotor (loss of senses, incoordination, paralysis
=degrades neurons and disrupts met
-Kidney = tubular damage from inorganic Hg
-Others = stomatitis, gingivitis, excess salivation
How is mercury toxicity diagnosed and treated?
-diagnosis made in lab
-inorganic mercury can be measured in 24h of urine
-organic mercury can be measured in blood
-treatment includes ending exposure; chelating agents enhance elimination
What drug increases mercury concentration in the brain?
dimercaprol
How are artificial sweeteners measured?
-on a sweetness scale relative to sucrose
-sucrose = 1
What are some artificial sweeteners and their sweetness?
-saccharin = 300x
-sucralose = 600x
-aspartame = 180x
What is saccharin?
-non-carb
-not metabolized by the body for energy
-discovered on accident
-human studies show safe
-findings found cancerous bladder tumors in rats = controversial
-epigenetic/promoter
-causes cell proliferation after high doses and long exposure
What does GRAS stand for?
generally recognized as safe
-prof says bullshit statement
What is aspartame?
-non-carb
-aspartic acid with phenylalanine and methyl ester
-dipeptide intermediate
-also discovered on accident
-does not satisfy cravings
-met into AA used for tyrosine synthesis, excess phenylalanine -> fumarate and acetoacetate for energy met
What products contain aspartame?
-breath mints
-soft drinks
-cereals
-gum
-candy
-ice creams
-drinkable yogurt
What are the safety concerns with aspartame?
-formaldehyde poisoning (methanol converts into formaldehyde
-formaldehyde = severe damage to the immune system, NS and genetic damage
Why do artificial sweeteners not satisfy sugar cravings?
-because they send false signals to the brain and when the body doesn’t receive the carbohydrates, the brain sends more signals
-this leads to increased cravings
what is acesulfame potassium?
-sweetener
-200x sweeter than sucrose
What is the ADI of acesulfame K set by the FDA?
-15mg/kg
-less than the amount that people take every day
What are some issues with acesulfame K?
-lack of long-term studies because FDA has not required them
-contains carcinogen methylene chloride
-methylene chloride can lead to mental confusion, liver effects, visual disturbances, and cancer
what is sucralose?
-aka Splenda
-newest sweetener
-no calories
-given GRAS
-FDA states non-carcinogenic and no neurological risk
-ADI = 5mg/kg
What are some risks with sucralose?
-has chlorine = carcinogenic
-lack of long-term studies
-study found rats had half the amount of good bacteria
What was the proposed accurate name for sucralose?
trichlorogalactosucrose
