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Boston University *
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705
Subject
Biology
Date
Feb 20, 2024
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docx
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EH705: Problem Set 2
20 Points
1. (5 pts)
Here is your opportunity to access and glean information from a Toxicological Profile developed by ATSDR. The profile for lead (Pb) can be found at: https://wwwn.cdc.gov/TSP/ToxProfiles/ToxProfiles.aspx?id=96&tid=22
. You may also find the ToxGuide useful: https://www.atsdr.cdc.gov/toxguides/toxguide-13.pdf
. Since the entire profile is 583 pages long (!), I would like you to focus your attention on Toxicokinetics section, found at: https://www.atsdr.cdc.gov/ToxProfiles/tp13-c3.pdf
. Use the information in this section to answer the following:
1.
(1 pt)
List two factors that affect GI absorption
of lead and then identify how those factors affect GI absorption. (Note that these do not include hand-to-mouth behavior, proximity to lead-containing surfaces, or inhalation rate, all of which affect a person’s exposure to lead but not absorption once in the body.)
The presence of food in the GI Tract affects GI absorption in that it decreases the absorption of lead. The GI absorption of lead is affected by the physiological state of the exposed individual, specifically the age of the exposed individual in that GI absorption of
lead is much higher in children at 40-50% compared to adults at 3-10%.
2.
(1 pt)
There are several chemical forms of lead (i.e., organic lead, inorganic lead). With dermal exposure, does the form affect absorption?
The form does affect the dermal absorption, with organic lead compounds having a higher dermal permeability than inorganic lead compounds
3.
(1 pt)
Rank the three main routes of exposure in terms of absorption of inorganic lead for adults.
Inhalation, oral, and dermal
4.
(1 pt)
What is the storage depot for lead? Once in the storage depot, can the lead be released again? If so, how?
The storage depot for lead is mostly bone, but also in soft tissue, of the exposed individual. The lead can be released into bloodstream via the bones, particularly in times
in calcium stress ( pregnancy or osteoporosis) and calcium deficiency (CDC, 2019)
1.
(5 pts)
Male Sprague-Dawley rats are used to evaluate the toxicity of DMDK (dimethyldoorknob). Each group consists of 10 animals, all the same age, size, and genetic background.
Materials and Methods
.
Experiment A. Male rats aged 21 days were given access to drinking water containing 2 µg/L DMDK, 4 µg/L DMDK, or 8 µg/L DMDK and fed Purina rat chow ad libitum
. Control rats of the same age were given tap water. Animals were dosed daily for 45 days.
Experiment B. Four groups of rats (same as in Experiment A) were treated as were the previous experimental groups, but the doses of DMDK were decreased. Animals were dosed daily for 45 days.
Experiment C. Three groups of rats were treated as were those in A & B, except that the animals in this experiment were dosed 3 days/week for 45 days.
Twenty-four hours after the final treatment, the rats were anesthetized and weighed. Blood was drawn by cardiac puncture, and the rats were euthanized. Blood was allowed to clot, and the serum was separated and frozen until assayed. Testis, epididymis (duct system that stores sperm) and seminal vesicles (gland of the male reproductive tract that secretes fluid that nourishes sperm) were dissected, weighed and frozen. Insulin-like factor 3 (INSL3) was assayed in each serum sample by means of an ELISA. The significance of the differences between control
and experimental groups was analyzed using an ANOVA with Dunnett’s test.
Results
Table 1: Effect of prolonged treatment of DMDK on organ weights and insulin-like factor 3 (INSL3) levels in male rats. No significant differences in testis weights were observed.
Body
Weight at
study
completio
n
(g)
Mortali
ty
Serum
INSL3
Level
(ng/
ml)
Epididymu
s Weight
(g)
Seminal
Vesicle
Weight
(% body
weight)
Experiment A
Control
408 ± 8
1/10
5.7 ±
0.9
1.16 ± 0.02
0.412 ±
0.017
DMDK 2 µg/L
396 ± 6
2/10*
5.6 ±
0.6
0.95 ±
0.03*
0.237 ±
0.016*
DMDK 4 µg/L
391 ± 4
4/10*
5.6 ±
0.3
0.90 ±
0.02*
0.150 ±
0.008*
DMDK 8 µg/L
350 ± 3
5/10*
4.0 ±
0.2*
0.85 ±
0.03*
0.125 ±
0.006*
Experiment B
Control
410 ± 7
0/10
5.9 ±
0.2
1.18 ± 0.03
0.392 ±
0.011
DMDK 0.1 µg/L
410 ± 15
1/10
5.7 ±
0.4
1.20
± 0.05
0.397 ±
0.015
DMDK 0.5 µg/L
409 ± 8
1/10
5.7 ±
0.3
1.11
± 0.02
0.356 ±
0.022*
DMDK 1 µg/L
403 ± 6
0/10
5.8 ±
0.9
0.98 ±
0.05*
0.341 ±
0.008*
Experiment C
Control
427 ± 9
1/10
6.0 ±
0.5
1.02 ± 0.03
0.390 ±
0.025
DMDK 1 µg/L
423 ± 7
0/10
5.7 ±
0.5
1.06 ± 0.02
0.395 ±
0.016
DMDK 2 µg/L
416 ± 9
0/10
5.9 ±
0.4
0.99 ±
0.02*
0.360 ±
0.012*
* p < 0.01, compared to control
1.
(1 pt)
If only experiment A were done, can you conclude that DMDK is a male reproductive toxicant. Why or why not?
Yes! This is because there is a strong positive association between the DMDK and
a decrease in both epididymis and seminal vesicle body weight, giving evidence to the idea that DMKDK is a male reproductive toxicant.
2.
(2 pt)
Why was Experiment B conducted? And, what can you conclude based on the results?
Experiment B was conducted to see if lower levels of DMDK had similar effects, if any at all, to Experiment A.
3.
(1 pt)
What can you conclude about the toxicity of DMDK in light of Experiment C? Why?
It is a toxic chemical, but at lower levels does, has less severe adervse outcomes and less
weight fluctuations in the epididymis and seminal vesicles.
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4.
(1 pt)
When you examine the results from Experiments A, B & C, what do you conclude about the toxicity of DMDK in this system?
Given the overall decrease, in each experiment, of both epididymis and seminal vesicle body weight, I would conclude DMDK is significantly toxic.
2.
(5 pts) You have been asked to evaluate the toxicity of two anti-caking agents added to road salt. Note that cyanide is often present with the anti-caking agent used in Boston, and towering piles of salt are stored in the open in Chelsea.
Table 2: Dose-Response Data for Orally Administered Agent A
Dose (mg/kg)
Mortality (%)
0.1
1
0.25
2
0.5
8
1
25
2
45
5
75
10
98
15
100
Table 3: Dose-Response Data for Orally Administered Agent B
Dose (mg/kg)
Mortality (%)
12
0
30
5
60
35
90
60
120
80
180
95
240
100
a.
(2 pt) Graph the dose-response curves for Agents A & B based on the data presented below so that you may determine toxicological parameters from them (feel free to use Excel, R or other graphing program).
b.
(1 pt) Using the dose-response curves themselves (no curve fitting programs, please), what are the approximate LD
50
s for Agent A and Agent B? Be sure to indicate HOW the values were determined.
The Lethal Dose 50 (LD50) is the dose that results in the death of 50% of the population, therefore the LD50 for Agent A is ~2mg/kg and the LD50 for Agent B is ~75mg/kg. To determine the LD50, I read from where the 50% point intercepts the dose.
c.
(1 pt) Which of the two is more acutely toxic? How do you know?
Agent A is more acutely toxic as the steepness of teh slope is much greater, and it has a
lower LD50.
d.
(1 pt) In words that your roommate can understand, describe what an LD
50
is and
how it is determined– in no more than three sentences.
The Lethal Dose 50 (LD50) is a dose of a toxicant that results in the death of 50% of the population.
3.
(5 pts)
Rats were exposed to perfluorooctanoic acid (PFOA) via various routes and the concentration of PFOA in blood was followed so that the Area Under the Curve (AUC) was determined. Using the data shown below, answer the following questions.
Table 4: Bioavailability parameters for PFOA
Medium/
Route of exposure
PFOA (mg/kg)
Average Rat
Weight (g)
AUC
(mg●hr/L)
PBS/Intravenous
1
400
450
PBS/Inhalation
2
322
572
PBS/Dermal
15
302
63
Feed/Oral
1.5
376
556
1.
(2 pts) What is the absolute bioavailablity of PFOA with each exposure route? Show your
work.
Intravenous = F = F^IV / F^IV = AUC^IV /AUC^IV * Dose ^IV / Dose^IV = (450 / 450) * (1 /
1) = 1
Inhalation: F = F^Exp / F^IV = AUC^Exp /AUC^IV * Dose ^IV / Dose^Exp = (572 / 450) * (1
/ 2) = 0.64
Dermal: F = F^Derm / F^IV = AUC^Derm /AUC^IV * Dose ^IV / Dose^Derm = (63 / 450) *
(1 / 15) = 9.03 x 10^-3
Oral: F = F^Oral / F^IV = AUC^Oral /AUC^IV * Dose ^IV / Dose^Oral = (556 / 450) * (1 / 1.5) = 0.82
2.
(1 pt) For which experimental
route of exposure is the bioavailability the highest? The lowest?
The highest was intravenous, followed by oral, then inhalation, and lastly dermal.
3.
(2 pts) Given these data and a similar total exposure
, would you expect that an occupational exposure or an every-day life exposure would result in a higher/lower/similar internal dose? Why?
I would expect an occupational exposure would result in a higher internal dose as workers who are exposed to such chemicals may have the an increase rate of consumption than people who only are exposed in every-day life may not have, specifically higher rates of PFOA, in additional to them having both types of exposure (occupational and everyday).
“Lead (PB) Toxicity: What Are Routes of Exposure to Lead?” Centers for Disease Control
and Prevention
, Centers for Disease Control and Prevention, 2 July 2019, https://www.atsdr.cdc.gov/csem/leadtoxicity/exposure_routes.html#:~:text=Once
%20absorbed%20into%20the%20body,%2C%20osteoporosis)%20or%20calcium
%20deficiency.
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