Distribution of Toxicants

Unit 5

Federico Sinche
[email protected]
Objectives:
• Recognize the main distribution pathways of
toxicants in the organisms
• Learn the functions of First-pass effect during
the distribution of toxicants
• Understand the roles of volume of distribution
and fat depot of toxicants in the body
Outline
• Volume of distribution
• Storage of toxicants in tissues
• Physiological barriers in the brain
• Maternal-unborn passage of toxicants
 Volume of Distribution
• Volume of distribution (Vd)
• The volume in which the contaminant (drug) would be dissolved in
order to produce the observed blood concentration
• The major body fluid is water
• Total body water
• Extracellular fluid (ECF)
• Plasma
Capillary endothelium
• Interstitial fluid & lymph
• Bone & dense connective
tissue water
• Transcellular (digestive secretions)
• Intracellular fluid (ICF)
Electrolytes
Body Fat

Body water

Ref.: Kamel et al. 2010

 Volume of Distribution Cont’d
• Plasma
• Circulate in the blood vessels
• Interstitial fluid
• Bathes all tissue cells except for the blood elements
• Water movement between ECF and ICF
• ECF and ICF fluids at EQUIL
• No EQUIL
• Lower solute conc → water → greater solute conc → EQUIL

(55% of total blood)

(<1% of total blood)

(45% of total blood)

Ref.: Kamel et al. 2010; http://givingblood.org/about-blood/blood-components.aspx

 Volume of Distribution Cont’d

Ref.: Kamel et al. 2010

POLL 1
 Storage of Toxicants in Tissues Cont’d
• Fat as storage depot
• Lipophilic toxicants (↑Kow)
• Storage lowers the conc of the toxicant in the target organ
• The expected toxicity vary upon fat content in the organism
• Short-term starvation
• ↑ Intoxication
• ↑ Mobilization of fat

Any chemical in a storage depot is in EQUIL with the free fraction

of toxicant in plasma,
thus it is released into the circulation as the unbound fraction
(bioavailability) of toxicant is eliminated

Effects of High Fat-High

Sugar (HFHS) and Vit D
supplementation on lipid
accumulation
In the mouse gastrocnemious

Ref.: Kamel et al. 2010

 Storage of Toxicants in Tissues Cont’d
• 26 organochlorine
compounds (pesticides
and PCBs)
• Organochlorine body
burden
• Blood samples
• Subcutaneous adipose
tissue samples

• Obese individuals
• Hypocaloric diet
during 15 weeks
• Control individuals
• Mean body wt loss
9.5 kg

Ref.: Chevrier et al. 2000

 Storage of Toxicants in Tissues Cont’d
• Plasma proteins as storage depot
• Plasma proteins and physiologic constituents of the body bind to
xenobiotics
• Protein-ligand interaction occur due to
• Hydrophobic forces
• Hydrogen bonding
• Van der Waals forces

Ref.: Casarett & Doull’s 2015

 Storage of Toxicants in Tissues Cont’d
• Liver and kidney as storage depots
• High capacity for binding a multitude of chemicals
• Concentrate more toxicants than the rest of organs
• Ligandin (glutathione S-transferases NB) proteins → affinity for organic
xenobiotics
• Bilirubin (pigment protein) in plasma
• Some bilirubin → Hepatocyte
• Intracellularly → bilirubin binds to ligandin
• Bilirubin is either conjugated and excreted
into to bile or returned to the plasma without
conjugation

Ref.: https://www.rcsb.org/structure/1K3O
 Storage of Toxicants in Tissues Cont’d
• Metallothionein (MT) proteins → affinity for metals
• Induced by metals (MT gene expression)
• Sulfur-rich protein (-SH)
• Cystein residues (Cd vs Cu+2)
• Non-enzymatic proteins
• Low molecular wt

Ref.: Salvaggio et al. 2017; https://phys.org/news; https://www.rcsb.org/

 Storage of Toxicants in Tissues Cont’d
• Metallothionein (MT) proteins-Detox
 Storage of Toxicants in Tissues Cont’d
• Bone as storage depot
• Uptake of xenobiotics via surface chemistry phenomenon
• Exchange between the bone surface of hydroxyapatite crystals and the
surrounding ECF
• Deposition and storage of toxicants
• Lead accumulation
• Fluoride deposition (skeletal fluorosis)
• Radioactie strontium (osteosarcoma)

Ref.: Rey et al. 2010; https://www.semanticscholar.org

 Physiological Barriers in the Brain
• Access to the brain is restricted by
• The BBB
• The Blood-cerebrospinal fluid barrier (BCSFB)
• Physiologic protection of the brain
1. Tightly joined capillary endothelial cells → prevent diffusion of polar compounds
2. Glial cell processes (astrocytes) secrete chemical factors that modulate
endothelial permeability
3. The protein concentration in the ICF is much lower than that in other body fluids →
limit the movement of water-insoluble compounds
4. ATP-dependent transporters (ABC and SLC families)
• Efflux transporters MDR1, BCRP and MRP1, 2, 4 AND 5 → move xenobiotics back into the
blood for detoxification
• The blood cerebrospinal fluid (CSF) forms a barrier, and the efflux transporters protect
against toxicant distribution into the CNS
 Physiological Barriers in the Brain Cont’d
The barriers are not fully
developed at birth

Chemicals more toxic to

newborns than to adults

Ref.: https://brainbarriers4you.eu/csf_brain_en.html
 Physiological Barriers in the Brain Cont’d

Ref.: May and Gosssage 2001; http://creatinghopeafrica.com/fas-awareness/

 Maternal-Unborn Passage of Toxicants
• Passage of toxicants across the placenta
• The placenta is a temporal organ that consists of a number of cell layers
(at most six) interposed between the fetal and maternal circulations
• Vitamins, amino acids, essential sugars, iron, and calcium are transported by
active transport systems from mother to fetus
• More lipid-soluble substances attain a maternal-fetal at EQUIL
• The concs of toxicants in the plasma of the mother and the fetus the same at
steady-state conditions

Biotransformation enzymes

Fetuses have very little fat

Viruses (e.g., rubella virus), cellular

pathogens (e.g., syphilis
spirochetes), and globulin antibodies
can traverse the placenta

Ref.: https://www.malpracticeohio.com
 Maternal-Unborn Passage of Toxicants
Cont’d
• Fat composition from birth to 1 year

Ref.: Toro-Ramos et al. 2015

 Take Home Messages
1. Distribution of toxicants is influenced directly by
the site of action in the body
2. Adipose tissues can served as fat depot for
hydrophobic contaminants, however the
contaminants can be released to the plasma by
desorption or fat reduction
3. The BBB and BCSFB are physiological barriers
that prevent contaminants reaching the SNC
4. The parasite relationship between mother and
unborn can lead to passage of contaminants to the
new unborn organism
 References
Benetti, E., Mastrocola, R., Chiazza, F., Nigro, D., D’Antona, G., Bordano, V., ... & Minetto, M. A. (2018). Effects of vitamin D
on insulin resistance and myosteatosis in diet-induced obese mice. PLoS One, 13(1), e0189707.

Salvaggio, A., Pecoraro, R., Scalisi, E. M., Tibullo, D., Lombardo, B. M., Messina, G., ... & D'amante, G. (2017).
Morphostructural and immunohistochemical study on the role of metallothionein in the detoxification of heavy metals in Apis
mellifera L., 1758. Microscopy Research and Technique, 80(11), 1215-1220.

Toro-Ramos, T., Paley, C., Pi-Sunyer, F. X., & Gallagher, D. (2015). Body composition during fetal development and infancy
through the age of 5 years. European journal of clinical nutrition, 69(12), 1279-1289.

Klaassen, C. D., & Amdur, M. O. (Eds.). (2013). Casarett and Doull's toxicology: the basic science of poisons (Vol. 1236, p.
189). New York: McGraw-Hill.

Rey, C., Combes, C., Drouet, C., & Glimcher, M. J. (2009). Bone mineral: update on chemical composition and structure. Osteoporosis
International, 20(6), 1013-1021.

Kamel, K. S., Halperin, M. L., & Goldstein, M. B. (2010). Fluid, electrolyte and acid-base physiology e-book: a problem-based
approach. Elsevier Health Sciences.

Schwarzenbach, R.P., Gschwend, P. M., Imboden, D. M. Environmental Organic Chemistry. 2nd Edition. (2003). John Wiley &
Sons, Inc. Hoboken, New Jersey. Pgs 1327.

Ehlers, L. J., & Luthy, R. G. (2003). Peer reviewed: contaminant bioavailability in soil and sediment.

Jandacek, R. J., & Tso, P. (2001). Factors affecting the storage and excretion of toxic lipophilic xenobiotics. Lipids, 36(12),
1289-1305.

Chevrier, J., Dewailly, E., Ayotte, P., Mauriege, P., Despres, J. P., & Tremblay, A. (2000). Body weight loss increases plasma
and adipose tissue concentrations of potentially toxic pollutants in obese individuals. International journal of obesity, 24(10),
1272-1278.
 References Cont’d
May, P. A., & Gossage, J. P. (2001). Estimating the prevalence of fetal alcohol syndrome: A summary. Alcohol Research &
Health, 25(3), 159.

https://www.semanticscholar.org/paper/Nanometre-scale-hydroxyapatite-ceramics-for-bone-Poinern-
Brundavanam/dfa0cde957491ae762e0b34a0aef4359c3cd5d9a

USEPA. (1990). Ground water issue. Office of solid waste and emergency response. EPA/540/4-90/053.

https://phys.org/news/2017-03-heavy-metal-domain-cysteine-rich-protein.html

https://www.rcsb.org/3d-view/2MRT?preset=ligandInteraction&sele=CD

https://www.malpracticeohio.com/birth-injuries/placental-abruption/

http://givingblood.org/about-blood/blood-components.aspx

https://brainbarriers4you.eu/csf_brain_en.html

http://creatinghopeafrica.com/fas-awareness/