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Global biogeochemical element cycles (GBECs)

Chemistry 321 Environmental Chemistry

a global
biogeochemical
element cycle
describes
dynamic circulation of
elements between
the

Fundamentals of Toxicological Chemistry

References:
Manahan chapter 2.9, 2.10, 2.13-2.16

Biosphere

Please read Manahan chapters 2.5-2.8 on your own

(lipids, nucleic acids, enzymes, metabolism)
"Introduction to Toxicology" by John Timbrell

Anthrosphere

Atmosphere
Hydrosphere
Geosphere
Biosphere

http://site.ebrary.com.ezproxy.lib.ucalgary.ca/lib/ucalgary/detail.action?docID=10267636

Hites & Raff, chapter 7

CB/MC 5th edition, pp 584-596

and since human

activities emit
chemical
elements the
Anthrosphere.

Further reading:
"Introduction to Environmental Toxicology" by Landis & Yu

Sept 24, 2015

Atmosphere

Geosphere

Hydrosphere

139

Objectives

140

Bioaccumulation, bioconcentration, and biomagnification

Following this unit, you are expected to be able to:

define the terms bioaccumulation, biomagnification, bioconcentration,

and Kow
list types of toxic substances, toxin mode-of-entries, and toxin
removal pathways
list and explain types of toxic responses
interpret dose-response relationship graphs
define the terms efficacy, toxicity, lethality, LD50, TD50, ED50
define the terms additive, synergistic, and antagonistic response
calculate bioconcentration factors, No Observable Effects
Levels (NOEL), and Acceptable Daily Intakes

Bioaccumulation
Biomagnification
Bioconcentration

141
Baird, C., Cann, M.C., 2008. Environmental chemistry, 4th ed. W.H. Freeman, New York.

Biomagnification

Measuring hydrophobicity: Kow

biomagnification

a chemical is allowed to equilibrate between two liquid layers of water and

1-octanol
Example:

The partitioning coefficient (Kow) is defined by

K ow =

[S]oc tanol
[S]water

The square bracket denote concentrations of the substrate S in molarity

(moles/liter)

Another example:

typically reported as a log value (log Kow)

can be function of temperature
if value is large:

Q. Why useful?

A large Kow value implies a tendency for a

compound to bio-accumulate (in fatty tissue
of the animal), while a small value suggests
that it will remain in the ambient environment

if value is small:

Baird, C., Cann, M.C., 2008. Environmental chemistry, 4th ed. W.H. Freeman, New York.

143
143

http://toxics.usgs.gov/definitions/kow.html
CB/MC 4th edition pp 425-426; 5th edition pp 584-587
Hites & Raff, pg 229

144

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Toxicology

Types of toxic substances

- study of harmful interactions between chemicals + biological systems

- science that defines limits of safety of chemicals
What do toxicologists do?

Types of exposure

Speed

Mode of entry
Do we need toxicology?

Removal
145

Types of toxic substances

146

Philosophy of pharmacy
Philippus Theophrastus Aurelous Bombastus von Hohenheim "Paracelcus"
(1493-1541)

Speed

A poison in the body can be cured by a similar poison

but the dosage is very important:

Types of exposure

"All substances are poisons; there is none that is not a poison.

http://upload.wikimedia.org/wikipedia/commons/8/83/300704_beratzhausen-oberpfalz-paracelsus-denkmal_1-480x640.jpg

Mode of entry

crucial concept to the safe use of drugs

assessment of threshold doses and safe and non-toxic levels
implies that even seemingly harmless substances such as table salt can be
dangerous under certain conditions

Removal

Example: Drinking too much water can kill you.

http://www.sciam.com/article.cfm?id=strange-but-true-drinking-too-much-water-can-kill
Socrates drinking Hemlock

147

148

Figure 1.2 - Introduction to Toxicology" by J. Timbrell

Dose-response relationship

Efficacy, toxicity, lethality

response: death or pathological lesions

e.g., a pharmaceutical drug

e.g., liver cell: necrosis;

- a more precise response is a biochemical, pharmacological or chemical change
Two types:

LD50 = dose at which

50% of test animals die
TD50 =

dose: mg (mg or ng) substance/ kg body weight

Manahan 2.9.3
Figure 1.4 - Introduction to Toxicology" by John Timbrell

ED50 =

149

150
Figure 1.5 - "Introduction to Toxicology" by John Timbrell

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Comparing toxicity of substances

Comparing toxicity of substances

151

Comparing toxicity of substances

152

Examples of LD50
= dose at which 50% of test animals died

neurotoxin
in pufferfish
(blocks Na+)

153
Figure 1.6 - Introduction to Toxicology" by John Timbrell

154
Table 1.1 - Introduction to Toxicology" by John Timbrell

Example: Beer

Toxicity depends on route of administration

e.g., 75 kg human; drinking beer

LD50 of ethanol = 10,000 mg kg-1
=> need to consume 750 g of pure alcohol
beer has 5.5% alcohol; density ~1 g/mL
=> lethal amount ~ 13.6 kg 27 pints of beer
=> if you binge-drink, you're much closer to death than you realize!
(alcohol is very bad for you: weight gain, retardation, cancer, etc.)
sleeping anti-tuberculosis
aid
medication
(barbiturate)
1
2

local
anesthetic

mouse toxicity
rabbit toxicity

Note: not all mammals will necessarily have the same response to a particular substance;
e.g., paracetamol (tylenol) rapidly induces liver damage to cats (not as rapidly in humans or rats)
155

156
Table 1.1 - Introduction to Toxicology" by John Timbrell

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Toxic compounds in the body: Metabolism

Types of toxic responses

distribution will depend on water-solubility of the compound

water-soluble (hydrophilic) substances (e.g., metal ions) are removed via
blood stream kidney urinary tract
fat-soluble (hydrophobic) accumulate in fatty tissue bioaccumulation (e.g., DDT)

Direct toxic action

-

Body will try to oxidize foreign compounds (usually in liver) to make them more water-soluble.

Biochemical lesions
Pharmacological/physiological effects
Immunotoxicity
Teratogenicity
-

This can sometimes lead to "toxication":

Genetic toxicity
-

e.g.,
e.g.,
e.g.,
body is also capable of reduction, hydrolysis, hydration, glucuronidation, sulphation, acetylation,
glutathione conjugation, amino acid conjugation, and methylation reactions
157

Carcinogenicity
-

Selective toxicity

Animal testing
many millions of mice and rats have been "destroyed" in the name of science
are there alternatives?

very important concept!

Differences in susceptibility to toxic effects between:

Reasons:

158

to predict toxicity of
compound in humans
based on studies in
another species always
very difficult

Examples:
active against rats because
they have a receptor in smooth
muscle that humans lack
interferes with synthesis
of cell wall of bacteria

Nature Reviews Drug Discovery

4, 35-44 (January 2005)

http://pubs.acs.org/isubscribe/journals/cen/85/
i39/html/8539sci5.html

http://dx.doi.org/10.1038/nrd1606

advantages of using fish

small & inexpensive to maintain
produce hundreds of offspring
transparent monitor developing fish
compounds diffuse into fish
simplifies drug administration
have most organs of mammals
160

http://www.nature.com/nrd/
journal/v4/n1/full/nrd1606.html

159

Concept of synergism/antagonism

Types of toxic substances

Pharmaceuticals (drugs)
Food additives
Industrial chemicals
Environmental pollutants
Natural toxins
Household poisons

Reality:
exposure to chemicals rarely (if ever) limited to a single substance
usually mixtures of compounds

The toxicity of two compounds can be:

additive
synergistic
e.g.,
antagonistic
e.g.,
e.g.,

161

high doses of aspirin interfere with ATP production increased utilization of O2 and
production of CO2 hyperventilation
"Tinnitus is the medical term for roaring, buzzing, clicking, whistling, hissing, or high pitched
162
ringing in the ears or inside the head." (http://www.hearusa.com/hearing/index.asp?p=tinnitus)
Table 5.1 - Introduction to Toxicology" by John Timbrell

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Tylenol (paracetamol)

Thalidomide
"normal" pathways:
sulphate and glucoronic acid
some oxidation by cytochrome P-450
toxic metabolite reacts with glutathione
no problem
cats have a problem
According to wikipedia: Cats lack
glucuronyl transferase enzymes

sedative drug prescribed to pregnant women to treat morning sickness

late 1950s and early 1960s
first example of major drug induced toxicity
lead to characteristic limb deformity
now known to be a very potent teratogen
back on the market to treat leprosy (strictly controlled) and cancer
A teratogen is an agent that can cause malformations of an embryo or fetus.
http://www.thalidomide.ca/en/information/what_is_thalidomide.html

Overdose: LD50 ~ 340 mg/kg

"normal" pathways are saturated
(especially sulphate)
and cofactors are depleted
more paracetamol is oxidized to
N-acetyl-p-benzonequinone imine
eventually, there is a shortage in glutathione
tissue damage (necrosis)
Humans cannot live w/o a functional liver.

163

Drugs in rivers

164

Types of toxic substances

growing controversy: many common pharmaceuticals are found in rivers

links to sterility/feminization in male fish have been established
e.g., Hirsch, R., et al. (1999), Occurrence of antibiotics in the aquatic environment, Sci. Total
Environ., 225(1-2), 109-118. http://dx.doi.org/10.1016/S0048-9697(98)00337-4

Pharmaceuticals (drugs)
Food additives
Industrial chemicals
Environmental pollutants
Natural toxins
Household poisons

endocrine disruption: http://www.ec.gc.ca/eds/fact/eds_e.pdf

issues:
- bacterial resistance
- fertility (amphibians)
- (unknown) toxicity
....

Many types of food additives:

preservatives
- benzoates
- propionates
sorbates
nitrites/nitrates/nitrosamines
antioxidants
flavours
potentiators/MSG
sweeteners; aspartame, cyclamate, saccharin
colours
acidity controllers
anti-caking agents, stabilizers, thickeners
antibiotics

won't go into details

165

Food additives and contaminant examples

166

Additives in food "production"

added to change color/flavor/prevent spoilage/change

nature of foodstuff usually low biological activity

Example: growth promoter in chicken + increased egg production (since 1940s):

many potentially toxic substances (such as contaminants) naturally occur in food

or result from cooking

approved
as animal
feed additives
in US and
Canada

Examples:
tetrodoxin (natural toxin in puffer fish)
sulfites (added to wine and meat)
immunosuppression from certain food colorants
Science 2005, 309, 1735 http://dx.doi.org/10.1126/science.1113640
http://www.sciencemag.org/content/309/5741/1735

drugs used in veterinary practice must also be considered since humans consume meat
from animals treated with these drugs

acrylamide in potato chips

http://www.hc-sc.gc.ca/fn-an/securit/chem-chim/food-aliment/acrylamide/acrylamide_and_food-acrylamide_et_aliment-eng.php

many other substances added to animal feed: e.g., growth hormones

"You are what you eat."

167

168

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List of approved food additives and contaminants (GRAS)

gras = generally recognized as safe
http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/
ANTI-CAKING AGENTS
Aluminum calcium silicate
Calcium silicate
Magnesium silicate
Sodium aluminosilicate
Sodium calcium aluminosilicate
Tricalcium silicate
CHEMICAL PRESERVATIVES
Ascorbic acid
Ascorbyl palmitate
Benzoic acid
Butylated hydroxyanisole
Butylated hydroxytoluene
Calcium ascorbate
Calcium propionate
Calcium sorbate
Caprylic acid
Dilauryl thiodipropionate
Erythorbic acid
Gum guaiac
Methylparaben
Potassium bisulfite
Potassium metabisulfite
Potassium sorbate
Propionic acid
Propyl gallate
Propylparaben
Sodium ascorbate
Sodium benzoate
Sodium bisulfite
Sodium metahisulfite
Sodium propionate
Sodium sorbate
Sodium sulfite
Sorbic acid
Stannous chloride
Sulfur dioxide
Thiodipropionic acid
Tocopherols

EMULSIFYING AGENTS
Cholic acid
Desoxycholic acid
Diacetyl tartaric acid esters of (M)mono- and diglycerides
Glycocholic acid
Mono- and diglycerides
Monosodium phosphate derivatives of above
Propylene glycol
Ox bile extract
Taurocholic acid
NUTRIENTS AND DIETARY SUPPLEMENTS
Alanine
Arginine
Ascorbic acid
Aspartic acid
Biotin
Calcium carbonate
Calcium citrate
Calcium glycerophosphate
Calcium oxide
Calcium pantothenate
Calcium phosphate
Calcium pyrophosphate
Calcium sulfate
Carotene
Choline bitartrate
Choline chloride
Copper gluconate
Cuprous iodide
Cysteine
Cystine
Ferric phosphate
Ferric pyrophosphate
Ferric sodium pyrophosphate
Ferrous gluconate
Ferrous lactate
Ferrous sulfate
Glycine
Histidine

Inositol
Iron. reduced
Isoleucine
Leucine
Linoleic acid
Lysine
Magnesium oxide
Magnesium phosphate
Magnesium sulfate
Manganese chloride
Manganese citrate
Manganese gluconate
Manganese glycerophosphate
Manganese hypophosphite
Manganese sulfate
Manganous oxide
Mannitol
Methionine
Methionine hydroxy analogue
Niacin
Niacinamide D-pantothenyl alcohol
Phenylalanine
Potassium chloride
Potassium glycerophosphate
Potassium iodide
Proline
Pyridoxine hydrochloride
Riboflavin
Riboflavin-5-phosphate
Serine
Sodium pantothenate
Sodium phosphate
Sorbitol
Thiamine hydrochloride
Thiamine mononitrate
Threonine
Tocopherols
Tocopherol acetate
Tyrosine
Valine

List of approved food additives and contaminants (GRAS)

gras = generally recognized as safe

Vitamin A
Vitamin A acetate
Vitamin A palmitate
Vitamin B12
Vitamin D2
Vitamin D3
Zinc sulfate
Zinc gluconate
Zinc chloride
Zinc oxide
Zinc stearate
SEQUESTRANTS
Calcium acetate
Calcium chloride
Calcium citrate
Calcium diacetate
Calcium gluconate
Calcium hexametaphosphate
Calcium phosphate. monobasic
Calcium phytate
Citric acid
Dipotassium phosphate
Disodium phosphate
Isopropyl citrate
Monoisopropyl citrate
Potassium citrate
Sodium acid phosphate
Sodium citrate
Sodium diacetate
Sodium gluconate
Sodium hexametaphosphate
Sodium metaphosphate
Sodium phosphate
Sodium potassium tartrate
Sodium pyrophosphate
Sodium pyrophosphate, tetra
Sodium tartrate
Sodium thiosulfate
169
Sodium tripolyphosphate
Stcaryl citrate
Tartaric acid

Food additives and contaminants

STABILIZERS
Acacia (gum arabic)
Agar-agar
Ammonium alginate
Calcium alginate
Carob bean gum
Chondrus extract
Ghatti gum
Guar gum
Potassium alginate
Sodium alginate
Sterculia (or Karava) gum
Tragacanth
MISCELLANEOUS
Acetic acid
Adipic acid
Aluminum ammonium sulfate
Aluminum potassium sulfate
Aluminum sodium sulfate
Aluminum sulfate
Ammonium bicarbonate
Ammonium carbonate
Ammonium hydroxide
Ammonium phosphate
Ammonium sulfate
Bees wax
Bentonite
Butane
Caffeine
Calcium carbonate
Calcium chloride
Calcium citrate
Calcium gluconate
Calcium hydroxide
Calcium lactate
Calcium oxide
Calcium phosphate
Caramel
Carbon dioxide

Carnauba wax
Citric acid
Dextrans
Ethyl formate
Glutamic acid
Glutamic acid hydrochloride
Glycerin
Glyceryl monostearate
Helium
Hydrochloric adic
Hydrogen peroxide
Lactic acid
Lecithin
Magnesium carbonate
Magnesium hydroxide
Magnesium oxide
Magnesium stearate
Malic acid
Methylceliulose
Monoatmmonium glutamate
Monopotassium glutamate
Nitrogen
Nitrous oxide
Papain
Phosphoric acid
Potassium acid tartrate
Potasium bicarbonate
Potassium carbonate
Potassium citrate
Potassium hydroxide
Potassium sulfate
Propane
Propylene glycol
Rennet
Silica aerogel
Sodium acetate
Sodium acid pyrophosphate
Sodium aluminum phosphate
Sodium bicarbonate

Sodium carbonate
Sodium citrate
Sodium carboxy-methylcellulose
Sodium caseinate
Sodium citrate
Sodium hydroxide
Sodium pectinate
Sodium phosphate
Sodium potassium tartrate
Sodium sesquicarbonate
Sodium tripolyphosphate
Succinic acid
Sulfuric acid
Tartaric acid
Triacetin
Triethyl citrate

ethyl ester
Piperonal
Vanillin

SYNTHETIC FLAVORING SUBSTANCES

Acetaldehyde
Acetoin
Aconitic acid
Anethole
Benzaldehyde
N-butyric acid
d- or l-Carvone Cinnamaldehyde
Citral
Decanal
Diacetyl
Ethyl acetate
Ethyl butyrate
Ethyl vanillin
Eugenol
Geraniol
Geranyl acetate
Glycerol tributyrate Limonene
Linalool
Linalyl acetate
l-Malic acid
Methyl anthranilate
3-Methyl -3-phenyl glycidic acid

170

Types of toxic substances

Pharmaceuticals (drugs)
Food additives
Industrial chemicals
Environmental pollutants
Natural toxins
Household poisons

"Benzene production from decarboxylation of benzoic acid in the presence of

ascorbic acid and a transition-metal catalyst"
J. Agric. Food Chem. 1993, 41, 693
http://pubs.acs.org/doi/abs/10.1021/jf00029a001
see also http://pubs.acs.org/cen/news/84/i17/8417notw2.html

may be direct hazard at workplace

where they are used/formulated/
manufactured

"The combination of ascorbic acid and sodium benzoate in foods and

beverages should be evaluated more carefully, in view of these results."

e.g., exposure to solvents

exposure often regulated by
law, but realistic levels may still
prove hazardous in long term

hematotoxicity = chemically
induced toxicity of the blood

http://www.sciencemag.org/content/306/5702/1774.full
Science 3 December 2004:
Vol. 306 no. 5702 pp. 1774-1776
DOI: 10.1126/science.1102443

171

Industrial disasters

172

Types of toxic substances

frequently, chemicals are released accidentally by industry

in Bhopal, India, ~20,000 died as a result of exposure to methyl isocyanate from a
Union Carbide owned pesticide plant (in 1984)
methyl isocyanate = intermediate in the production of carbaryl
many other examples of such disasters

Pharmaceuticals (drugs)
Food additives
Industrial chemicals
Environmental pollutants
Natural toxins
Household poisons

- ozone
- aerosols and other airborne particulate matter
- acid rain
- lead, arsenic, and mercury (later lecture)
- herbicides and pesticides (next two lectures)
- many, many more

Figure 1.3 - Introduction to Toxicology" by John Timbrell

173

174

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Types of toxic substances

Pharmaceuticals (drugs)
Food additives:
Industrial chemicals
Environmental pollutants
Natural toxins
Household poisons

A "natural" toxin: ricin

many plants/animals produce toxic substances for defensive/

offensive purposes wide variety of chemical types & resulting toxic effects

ricin = highly toxic plant product

castor oil seeds

natural is safe is often far from truth since some of the most
toxic substances are of natural origin
contamination of food/accidental ingestion/stinging

first mention of Se
poisoning by a Se
accumulating plant
~1200

http://www.globalsecurity.org/wmd/intro/images/ricin-castor.jpg

unique toxicity
1 molecule kills 1 cell

175

Mechanism:
B-chain hooks onto cell (binds to a glycoprotein)
endocytosis
A+B chains separate and A chain enters cytoplasm
A chain catalytically blocks ribosome inactivates
1500 ribosomes a minute

after 9/11, ricin was the "scare du jour" for some time

http://pubs.acs.org/doi/abs/10.1021/cr60090a001

Types of toxic substances

http://www.wiley.com/legacy/college/boyer/
0470003790/cutting_edge/molecular_recognition/

used by Bulgarian secret police to kill Georgi Markov in London (1978)ricin.gif

no poison found very potent poison had been used;
tiny metal pellet recovered from his leg; inflicted by umbrella

176

New challenges to toxicology

Pharmaceuticals (drugs)
Food additives
Industrial chemicals
Environmental pollutants
Natural toxins
Household poisons

carbon monoxide
antifreeze
alcohol
glue
solvents (paints)
lead (wall point)
medicine cabinet

'traditional' studies have focused on high, one-time doses with

immediate response

While adequate for pharmaceuticals or "classic" poisons (e.g., pain

killers, Arsenic, etc.) these studies often do not capture:
- toxic effects of metabolites
- effects of continuous, long-term exposure to low levels of the toxin
e.g., effects on life expectancy and offspring

Emerging challenges:

issue of synergistic responses aggregate effects of long-term

exposure to many thousands of (bioaccumulative) substances is
virtually unstudied!

issue of new materials (e.g., silver nanoparticles in laundry detergent):

are methods to assess toxic effects adequate?

177

Example calculation: Kow and bioconcentration factor

Calculate the concentration of polychlorinated biphenyls (PCBs) that would
bioconcentrate into fish if the concentration of PCBs in ocean water is
0.05 pg L-1.
The density of ocean water is 1.0 kg/L, log Kow = 7.11 for PCBs, and fish
have 5.0% body fat. Assume that the fish has the same density as the
surrounding water.

179

178

NOEL and ADI

"Calculate the No Observable Effects Level (NOEL) and
Acceptable Daily Intake (ADI; also called toxicity reference dose,
or RfD)"

180