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a. Identify the sources of BPA exposure at the population level.
- BPA is used as a monomer in the manufacture of polycarbonates and epoxy resins, as an antioxidant in PVC plastics and as an inhibitor of end polymerization in PVC.
i. Polycarbonate: BPA is used in compact disc manufacture, food contact container (e.g. returnable milk and water bottles as well as baby feeding bootles), plastics dinnerware, medical devices, sport safety equipment and the car industry.
ii. Epoxy resin: BPA is used in protective coatings in food and beverage cans, food-processing application, structural composites, electrical laminates, electrical application and adhesives. Also used in some dental composites and sealants.
- BPA is used as an intermediate in different chemical reaction in the industry.
b. Identify the major and minor routes of exposure for BPA toxicity.
1. Major routes of exposure
- via contaminated food:
- Feeding bottles
- Food and beverage containers
- Epoxy resin food contact.
- Exposure occur when the ester bond in polycarbonate materials is hydrolyzed, releasing the monomer which can migrate into food and beverage products.
- The hydrolysis rate is increases:
- at high or low pH
- at high temperature
- by storage time (migrating BPA accumulate in canned food during storage)
2. Minor routes of exposure via environment:
- - Locally contaminated air
- - Aquatic environment
- - Soil
a. Children are identified as the highest exposure group.
b. because children still in a developmental process. So they are most susceptible to BPA.
a) Identify the physiochemical properties that may enhance BPA potential to cause toxicity
1) White solid at room temperature. Depending on the manufacturing process :
2) Vaporizes at 25C - due to low vapour pressure
3) Mild phenolic odour
4) Slightly water soluble
5) Solubility : 300mg/L
6) N-octanol - water partition coefficient (log Kow) is 3.32-3.64 - Not considered as bioaccumulation potential, since chemicals with a value between 4 and 7 bio accumulate to the greatest degree( BAIRD,2001)
7) Flash point varies - but is set to be circa 207C
8) Not explosive - But there's a risk for dust explosion
b) Since the characteristic of BPA is slightly water soluble, it can be said that half part of the compound is more to lipid soluble. Thus, it can easily cross the lipid bilayer even though it has a low bioaccumulation potential.
a. The systemic availability of parent compound of BPA or of its metabolite is lower following oral exposure is predictable because BPA shows extensive first pass metabolism in the liver.
b. Observation in question 4 (a) may diminish the toxicity of BPA because following oral exposure, the systemic availability is lower and therefore increase polarity of BPA. Increase in polarity will increase its water solubility and therefore increase secretion. Higher secretion will diminish its toxicity effect and kept the potential toxicity to a minimum level.
c. BPA metabolism is unlikely to yield a lot of intermediates because metabolism is catalyzed by enzymes and always found in the liver. The metabolism occurs rapidly as most foreign compound enter the body via the gastrointestinal tract and the portal blood supply goes directly to the liver. Besides, the enzymes are not specific for foreign compound and may have a major role in normal endogeneous metabolism.
d. Metabolite of BPA following metabolism:
a. BPA - sulphate
b. 5 - hydroxyl - BPA
e. The toxic potency of BPA metabolites compared to parent compounds is higher because it is all depends on polarity, water solubility that lead to rate of excretion of the metabolite. In this case, the toxic potency is higher because after metabolism, the polarity is decreasing and decreases its water solubility. Low water solubility of metabolites will make it difficult to excrete and remain in the body and increase its toxic potency.
a. Identify the metabolic reactions, enzyme that involved in BPA biotransformation.
Metabolism of BPA occurs at liver cell or also called hepatocyte. Metabolic reaction is glucuronidation. Enzyme that involved is Uridine 5'-diphospho-glucuronosyltransferase UDP-glucuronosyltransferase, UGT or glucuronyltransferase.
The glucuronidation of BPA, via the UDP-glucuronosyl transferases (GT), has been shown to be the major in vivo metabolic pathway for BPA in the rat, nonhuman primates, and human. This route of metabolism results in the production of BPA-monoglucuronide, a metabolite that has been shown to be devoid of estrogenic activity.
b. Predict if BPA is likely to undergo Phase 1 or Phase 2? Explain.
BPA is likely undergo Phase 2 reaction. Phase I reactions totally difference compared to phase 2 reaction. Phase 1 also termed nonsynthetic reactions may occur by oxidation, reduction, hydrolysis, cyclization, and decyclization reactions. Major enzyme involved in this phase is Cytochrome P450 monooxygenase system.
Phase 2 reactions usually known as conjugation reactions. For example if it is used with glucuronic acid, sulfonates. It is usually detoxication in nature, and involved the interactions of the polar functional groups. Enzyme that involved in this phase 2 reactions is transferees, for example UDP-glucuronosyltransferases.
The glucuronidation reaction consists of the transfer of the glucuronosyl group from uridine 5'-diphospho-glucuronic acid (UDPGA) to substrate molecules that contain oxygen, nitrogen, sulfur or carboxyl functional groups.
The hydroxyl moieties present on BPA provide functional group for glucuronidation. The resulting glucuronide is more polar (water soluble) and more easily excreted than the BPA, upon urination.
c. How does gender and age modulate BPA toxicity
BPA is age dependent. BPA-glucuronide and BPA concentrations in the plasma were greater in neonates than in adults suggesting an immaturity in the development of hepatic excretory function in neonatal rats. Nevertheless, the half-lives for the elim$ination of BPA-glucuronide in plasma were more rapid in neonatal animals than in adults. It is likely due to reduced microflora ß-glucuronidase activity and an absence of enterohepatic recirculation.
For gender, BPA can cross the placenta and presents in breast milk. So, it can affect the fetus and infant. Bisphenol A (BPA), an endocrine disruptor, is employed in the manufacture of a wide range of consumer products. The suggestion that BPA, at amounts to which we are exposed, alters the reproductive organs of developing rodents has caused concern. BPA blood concentrations were higher in male than in female fetuses. Here we demonstrate parent BPA in pregnant women and their fetuses. Exposure levels of parent BPA were found within a range typical of those used in recent animal studies and were shown to be toxic to reproductive organs of male and female offspring. The range of BPA concentration measured related to sex differences in metabolization of parent BPA.
d. What are the likely routes for BPA elimination from the body?
The likely route for BPA elimination are via faeces, urine and breast milk
e. Why would you expect BPA to be eliminated mainly via faecal remains in rats but not in humans?
Because BPA shows extensive first pass metabolism (mainly by glucoronide conjugation). Enterohepatic circulation ccurs in rats,it is something that not seen in humans.
f. Why would you expect BPA to penetrate maternal placental barrier?
There is a finding by Osamu Takahashi and Shinshi Oishi of the Tokyo Metropolitan Research Laboratory of Public Health, The findings show that the placenta fails to act as a barrier to a potentially toxic compound, 2,2-bis(4-hydroxyphenyl)propane, also known as bisphenol A or BPA. They discovered that BPA is absorbed and distributed in maternal internal organs and fetuses extremely rapidly.Chemicals with a lower log Pow (octanol/water partition coefficient), such as diethylstilbestrol and salicylic acid, are more hydrophilic and they more easily cross the placenta. The log Pow of BPA is 3.3, thus it crosses the placenta so rapidly.
a) Examine the LD 50 values of BPA from experimental data, how would you classify the acute toxicity potential of the chemical?
b) State the acute and chronic effects of BPA.
Acute effects includes skin irritation usually from an industrial sources, eye and nasal irritation reported by anecdotal company, as well as respiratory tract irritation from employee survey performed at Shell Oil Company.
There are no data available on studies in human for repeated exposure, mutagenecity, carcinogenicity or reproductive effects.
c) How did investigators deduce that BPA is a reproductive toxicant?
The critical effect of BPA exposure is in the EU risk assessment identified as the effects on development of reproductive organs which delayed vaginal patency in female and preputial separation in males after chronic administration.
d) Identify the key target organs for BPA toxicity.
After a long term exposure to BPA, the liver is identified as the target organ in mice, resulting in introduction of multinucleated giant cells. Studies from one laboratory indicating that exposure to BPA in the ug range can cause developmental effects on the male mice reproduction system, for examples, increased prostate weight and decreased efficiency.
e) Identify the sub organelle target for BPA toxicity.
Size and nuclei of hepatocytes are changed.
a. Study Table 1 in the review provided, female animals (pregnant and non pregnant) appear to be more susceptible to BPA toxicosis. Explain why, with references to the NOAEL and LOAEL values.
Based on Table 1,
Nagel et al.(1997) and Vom Saal et al.(1998)
Ashby et. Al (1999)
Cagen et al. (1999)
Tyl et al. (2002)
Female animals (pregnant and non pregnant) appear to be more susceptible to BPA toxicosis where the effect that can be seen were included regression in peripubertal development of the mammary gland, reduction of the weight of the vagina and the absolute volume of lamina propia in uterus.
As we can see from the table, for NTP 1985 study, the NOAEL cannot be determined. It's mean that we do not know the exact highest tested dose of a substance that has been reported to have no harmful effects on people or animals. It will lead to administration of higher dose that will cause harmful BPA toxicosis.
By using the NOAEL or LOAEL values, when dose response curve is extrapolated, it seems to cross the X-axis at the origin rather than at some positive value or dose level. This means that there is a response at all exposure levels tested and so within the limits of analytical techniques available, no safe exposure level can be seen with confidence. Furthermore, for an experimental study that produced a NOAEL, it will have stated the adverse effect to be observed before initiation. So, it tends to be safer. Because the absent of NOAEL data in NTP study, it is the reason why female animals appear to be more susceptible to BPA toxicosis.
(NOAEL) No Observed Adverse Effect Level is the highest tested dose of a substance that has been reported to have no harmful (adverse) health effects on people or animals.
(LOAEL) Lowest Observed Adverse Effect Level is the lowest tested dose of a substance that has been reported to cause harmful (adverse) health effects on people or animals.
b. Discuss how BPA uncertainty factor was achieved.
Uncertainty factor is a number (equal or greater than 1) used to divide NOAEL or LOAEL values derived from measurements in animals or small groups of humans, in order to estimate a NOAEL or LOAEL value for the whole human population. It is also called margin-of-safety (MOS).
Uncertainty factors are used to compensate for a deficiency in knowledge concerning the accuracy of test results and the difficulty in estimating the health effects in a different species and/or in different exposure conditions. As such, the value of the uncertainty factor depends on the nature of the toxic effect, the size and type of population to be protected, and the quality of the toxicological information, and includes scientific judgments.
In this case, BPA uncertainty factor can be achieved by comparing NOAEL and LOAEL to the estimated exposure level. The magnitude of MOS is then evaluated based on expert judgement to see if the exposure is of no relevance to human health, taking into account the different uncertainties in the underlying data. The MOS is estimated for the clinical effects for different subpopulation, such as effects on the liver and fertility as well as developmental effect.
Depending on the effect, the conclusion drawn in the risk characterization is different according to the site of exposure. For example, by using SCF opinion, TDI for female animal = 50/ 1000= 0.05mg/kg/day is compared to the estimated daily intakes ranging from 0.00048mg/kg/day for adults. It can be noted that TDI is not exceeded.
Another way to set exposure limit is by using Total Daily Intake calculation. This is the factor used to determine the safe intake for food additives and contaminants such as pesticides and residues of veterinary drugs and to establish the safe level in food.
Tolerable daily intake (TDI)
= No Observed Adverse Effect Level (NOAEL) Assessment Factor (AF)
a. Is BPA an endocrine disruptor?
Yes. BPA presenting the endocrine disrupt activity on the EU risk assessment document, range from 3 to 5 orders of magnitude less potent than estradiol. It also interferes with thyroid hormone in vitro.
b. Relate the statement “BPA is an example of a non-steroidal xenoestrogen” with the mechanism of BPA action.
Xeno- means foreign or different. BPA is a xenoestrogen, which is nonsteroidal chemical that can enter the body by ingestion or adsorption and mimic the actions of estrogens activity both in vivo and in vitro. However, its structure is different from the endogenous estrogens. As it imitates the estrogens, it can bind to nuclear estrogen receptors and induces transactivation of estrogen-responsive genes. It also has endocrine modulating and also has the ability to disrupt the normal functioning of the endocrine system (endocrine disrupting activity). In in vitro systems, BPA competes with estradiol (E2) for binding with the (estrogen receptor α) ERα and induces expression of progesterone receptor (PR) and proliferation of MCF-7 human breast cancer cells. Recently, the in vitro studies also showed the formation of estrogenically active metabolite of BPA, which is 4-methyl-2,4-bis(p-hydroxyphenyl)pent-1-ene (MBP) which is 200-fold more potent than BPA.
c. Why if BPA likely to delay puberty and retard spermatogenesis in males?
The major concern regarding this endocrine-disrupting chemical is with exposure during critical periods in organ development especially in the embryo, fetus, and newborn. It is because the development of the organ is coordinated by hormonal signals and disruption of these signals can lead to irreversible changes in organ function.There are studies indicating that exposure to BPA in the mcg-range can cause developmental effects on the male mice reproductive system. The effects may be increased prostate weight and decreased sperm efficiency. In report by Tyl et al, (2002) they proposed that the reduction in body weight gain is the reason to the delay of puberty (NOEAL: 50mg/kg bw/day).
d. With reference to additivity or antagonism, describe the nature of BPA interaction with estrogen.
BPA interaction with estrogen receptor is additive. It inteact by binding to the receptor and activate the transactivation of estrogen-responsive genes. ERα and other members of the steroid receptor family exhibit a common domain structure with distinct regions responsible for ligand binding, dimer formation, DNA binding, and transcriptional activation. Upon binding estrogen, the ER-estrogen complex is translocated into the nucleus, where it binds to estrogen-responsive genes. The estrogen-occupied receptor then interacts with additional transcription factors and components of the transcription initiation complex to modulate gene transcription.
a. Predict the percentage of A- a weak acid toxicant (pKa=4) that may absorbed across the gastric mucosa membrane (pH=2)
pH = pKa + log [A-]/[HA]
2 = 4 + log [A-]/[HA]
log [A-]/[HA] = 2 - 4
log [A-]/[HA] = -2
[A-]/[HA] = 0.01
% of A- = 0.01/(1+0.01) x 100%
% of HA absorbed = 100% - 0.99%
b. Predict the percentage of A that may ionize in the plasma (pH=7).
pH = pKa + log [A-]/[HA]
7 = 4 + log [A-]/[HA]
log [A-]/[HA] = 7 - 4
log [A-]/[HA] = 3
[A-]/[HA] = 1000
% of A- = 1000/(1000+1) x 100%
a) Discuss the toxicity of carbon tetrachloride with respect to bioactivation
b) Your answer should include all relevant chemical pathways and anticipated toxic end point.
Carbon tetrachloride is an important and widely used industrial solvent. It was formerly widely used in the household, in fire extinguishers, shampoo and dry cleaning. Earlier, CCI4 was even used therapeutically against infections by hook worms and in the nineteenth century solvent was used as an anesthetic and analgesic. After the high potential for acute toxicity became evident, all these applications obviously became obsolete. Nevertheless, intoxication with CCI4 still occurs, for example by accidental ingestion.
The major target organs of toxicity are the liver and kidney. In the first few hours of ingestion, slight to severe neurological disorders are prevalence (headache, visual disturbance, CNS depression, coma) but also gastrointestinal irritations (vomiting, diarrhea and bleeding). During the following day(s) liver and kidney toxicity develops. In the liver, toxicity is first manifested as steatosis (fatty change of the liver parenchyma) followed by centrilobular necrosis.
CCI4 is a small and lipophilic molecule and therefore readily distributes in the lipid compartments of the body. It is metabolized in the liver, and the clues to its toxicity lies in the CYP-mediated bioactivation of CCI4 and the induction of membrane lipid peroxidation.
Mechanisms Of CCI4- Induces Hepatoxicity:
CCI4 undergoes bioreductive metabolism catalyzed by CYP2E1 ( a rare reaction for CYPs) to the trichloromethyl radical. This CCI radical has been implicated in triggering the membrane lipid peroxidation chain reaction, as it abstracts a hydrogen form a fatty acyl residue, resulting in chloroform and an alkoxy radical formation. This is the major pathway, especially under condition of low pO2. In contrast, in the present of high oxygen tension, the trichloromethyl peroxy radical is formed. This is an extremely relative species that reacts and inactivates CYP2E1 itself (mechanism-based inactivation or suicide inactivation of CYP). The consequence is that the remaining CCI4 can no longer bioactivated because the CYP form involved is irreversibly damaged.
CCI4 toxicity is one of those examples that beautifully illustrate how a detailed understanding of the underlying mechanism of toxicity can help in developing therapeutics strategies in patients. For example an acute intoxication with CCI4 can be treated (within the first 24hours and before necrosis develops) by exposing the patients to hyperbaric oxygen to prevent further bioactivation and lipid peroxidation.
Reductive bioactivation of CCI4 leads to a reactive CCI3 radical which can react with fatty acyl residues and initiate lipid peroxidation. At high pO2, the CCI3-peroxy radical will destroy the bioactivating enzyme, CYP2E1 by suicide inactivation.