Poisons and Toxins

1. PHAR 719
Poisons and Toxins

2. PHAR 719 Presentation Schedule
Monday, May 24th (Week 9)
Final Exam after review
(exam opens at 3:15 pm;
40 min time limit)

3. PHAR 719 Week #8 Highlights
Avicide
DRC 1339, Starlicide® (3-chloro-4-methylaniline) – fairly selective toxicity
(nephrotoxicity) for starlings and related bird species; very low mammalian
toxicity

4. PHAR 719 Weeks #8 Highlights
Ciguatera Poisoning
The dinoflagellate toxins ciguatoxin and maitotoxin accumulate in
large tropical fish and are the causative agents of ciguatera
poisoning, a common type of fish poisoning in tropical areas
(paresthesias, arrhythmias, cramps and vomiting). Both of these
complex, non-protein toxins (ladder polyethers) are quite potent,
but fatalities are rare because the levels consumed are generally
insufficient to kill a human. Ciguatoxin affects sodium channels
and maitotoxin acts at calcium channels. Maitotoxin is claimed to
be the most potent of the non-protein toxins (50 ng/kg).

5. Lead follow-up
From 1976-1980 to 2015-2016, the geometric mean blood lead level (BLL) of
the US population aged 1 to 74 years dropped from 12.8 to 0.82 μg/dL, a
decline of 93.6%. Yet, an estimated 500 000 children aged 1 to 5 years have
BLLs at or above the blood lead reference value of 5 μg/dL established by the
Centers for Disease Control and Prevention. Low levels of exposure can lead
to adverse health effects. There is no safe level of lead exposure, and child
BLLs less than 10 μg/dL are known to adversely affect IQ and behavior. When
the exposure source is known, approximately 95% of BLLs of 25 μg/dL or
higher are work-related among US adults. Despite much progress in reducing
exposure to lead in the United States, there are challenges to eliminating
exposure.
“Control of Lead Sources in the United States, 1970-2017: Public Health Progress and Current Challenges to Eliminating Lead
Exposure”; Timothy Dignam, PhD, MPH, Rachel B. Kaufmann, PhD, MPH, Lauren LeStourgeon, MPH, and Mary Jean Brown, ScD,
RN; Journal of Public Health Management and Practice: January/February 2019 - Volume 25 - Issue - p S13-S22; doi:
10.1097/PHH.0000000000000889
1991 – Action level set at 10 microgram/deciliter
2012 - Level lowered to 5 microgram/deciliter in children (1-5
years)

6. Historical levels of concern for
comparison:
1970 – 40 mg/dL
1975 – 30 mg/dL
1985 – 25 mg/dL
1991 – 10 mg/dL
2012 – 5 mg/dL
Note – Over the past 50 years,
there is greater recognition
that even low lead levels can
have negative consequences;
hence the lowering of action
levels.

7. Study: Flint children's blood lead levels hit historic low in 2016
Kristen Jordan Shamus, Detroit Free Press, March 26, 2018
Blood lead levels in Flint's young children hit an all-time low in 2016, according to research
in the Journal of Pediatrics, suggesting that efforts to confront the city's water crisis are
making a difference in public health. The study analyzed 15,817 blood samples from
children ages 5 and younger beginning Jan. 1, 2006, and continuing through the crisis until
Dec. 31, 2016. Water filters, pipe replacements and a switch in the source of Flint's water
supply were among efforts to protect people from poisoning in the years since an April 2014
switch resulted in dangerous lead levels in drinking water.
In the study's 11-year span, the percentage of kids with blood lead levels of 5 micrograms
per deciliter, the level at which the U.S. CDC recommend intervention, fell from 11.8% to
3.2%. And the mean amount of lead in their blood samples also dropped — from 2.33
micrograms per deciliter in 2006 to 1.15 in 2016. The study showed an increase in blood
lead levels in young children from 2014-2015, at the peak of the water crisis, and an earlier
unexplained increase in 2010-2011. But by 2016, blood lead levels dropped lower than at
any point in the history of the city.
However, Flint isn't alone in dealing with the problem of lead exposure among children.
The researchers also noted that during the water crisis in Flint — when 3.75% of children
ages 5 and younger had blood lead levels higher than 5 micrograms per deciliter —
some other Michigan communities reported higher percentages of young children with
elevated blood lead levels: 5.1% of kids in Jackson, 8% in Grand Rapids and 7.5%
in Detroit. Statewide, 3.4% of children and 3.3% of kids nationally had lead levels above the
CDC reference point during the same period.

8. Palytoxin: History and Prehistory
David Malo, 1838, HAWAIIAN ANTIQUITIES, Translated from the Hawaiian by
N.E.Emerson, 1898, Bishop Museum Press, Special Publication 2, Second Edition, 1971,
Honolulu.
"In Muolea, in the district of Hana, grew a poisonous moss in a certain pool or pond
close to the ocean. It was used to smear on the spear points, to make them fatal. The
moss is said to be of a reddish color and is still to be found. It grows nowhere else
than at that one spot."
Ancient Legend: Again nighttime wails of anguish pierced the air above a small
Hawaiian fishing village on the island of Maui near the harbor of Hana. That evening,
when all the outrigger canoes had returned from the sea with the day's catch, yet
another fishermen was missing. Desperately seeking answers, the villagers placed the
blame on the hump-backed loner living in the cliff above.
Swarming up the ridge and ripping the tapa cloak from his back, they uncovered
gaping rows of triangular teeth within a huge mouth. They had caught a Shark God,
one with an insatiable lust for human flesh. Their suspicions were correct. Each day
after the canoes went out fishing, the hunchback had leisurely come past the village
and gone swimming for his breakfast.
The enraged fishermen mercilessly ripped the hunchback to pieces and burned him
completely. His ashes were thrown into a nearby tide pool. But, the continuing
malevolence of the demon slowly transformed the pond into a pool of death. Ugly
little brown anemones began to cloak its walls. Much later, it was found that these
"limu", when smeared on the tip of a daggar or spear, would perpetuate the evil of
the Shark God by bringing sure death to the victim. Thus, the stationary little animals
in the tide pool came to be known as the "Limu Make O Hana" (Seaweed of Death
from Hana).

9. Modern Legend:
By 1961, University of Hawaii researchers interested in local natural products had
discovered Malo's writings about a Hawaiian spear poison, Limu Make O Hana. Only
a few Maui natives remained who knew where the Limu Make O Hana grew, but none
would tell. Finally, after drinking enough Okole Maluna (a local brew from the ti
plant), one of them led the scientists to the sacred tide pool. As the biologists
prepared to take specimens, a group of natives interrupted them. These announced
that by an ancient curse the pond was "kapu", and warned that if anything was
disturbed, the evil of the curse would be activated. Smiling, the scientists said, "We
don't believe in superstition", and took their samples. Coincidentally, on that same
day a fire destroyed the main laboratory building of the Hawaiian Institute of Marine
Biology on Coconut Island in Kaneohe Bay, Oahu. The anenome samples taken,
proved to be a new species, which was named Palythoa toxica* and contained the
deadly poison, palytoxin.
*Walsh, G.E, & Bowers, R.L. (1971) A review of Hawaiian zoanthids with descriptions
of three new species. Zool. J. Linn. Soc., 50, 161-180.
Palytoxin possibly produced by symbiotic
dinoflagellates, Symbiodinium sp.; Related
toxins found in the dinoflagellate
Ostreopis siamensis

10. Marine Toxin - Palytoxin
MW = 2680; LD50 (mice; ip) = <100 ng/kg (50
ng/kg for maitotoxin, another marine toxin)
Symptoms
•Angina-like chest pains
•asthma-like breathing
difficulties
•tachycardia (racing pulse)
•unstable blood pressure
with episodes of low b.p.
•Hemolysis
Onset of Symptoms -
Rapid, with death
occurring within minutes
(based on animal models)
Antidote (in animals) –
Vasodilators are effective if
delivered immediately by
injection into the ventricle of the
heart.
Site of Action - Palytoxin targets the sodium-potassium pump protein by binding to the molecule such
that the molecule is locked in a position where it allows passive transport of both the sodium and
potassium ions, thereby destroying the ion gradient that is essential for most cells.
At the physiological level, the most sensitive target is the myocardium, or muscular component of the
heart, and the primary effect is vasoconstriction or rapid narrowing of blood vessels in the heart and in
the lungs. Another effect is hemolysis, or the destruction of the red blood cells. These three effects taken
together cut off the oxygen supply and the victim suffocates.

11. Palytoxin Found in Palythoa sp. Zoanthids (Anthozoa, Hexacorallia) Sold in the Home
Aquarium Trade
Jonathan R. Deeds,1* Sara M. Handy,1 Kevin D. White,1 and James D. Reimer2
1 United States Food and Drug Administration, 2University of the Ryukyus, Nishihara,
Okinawa, Japan, PLoS One 2011, 6, e18235.
Zoanthids (Anthozoa, Hexacorallia) are colonial anemones that contain one of the deadliest toxins
ever discovered, palytoxin (LD50 in mice 300 ng/kg), but it is generally believed that highly toxic
species are not sold in the home aquarium trade. We previously showed that an unintentionally
introduced zoanthid in a home aquarium contained high concentrations of palytoxin and was likely
responsible for a severe respiratory reaction when an individual attempted to eliminate the
contaminant colonies using boiling water. To assess the availability and potential exposure of
palytoxin to marine aquarium hobbyists, we analyzed zoanthid samples collected from local
aquarium stores for palytoxin using liquid chromatography and high resolution mass spectrometry
and attempted to identify the specimens through genetic analysis of 16S and cytochrome c
oxidase 1 (COI) markers. We found four specimens of the same apparent species of zoanthid, that
we described previously to be responsible for a severe respiratory reaction in a home aquarium, to
be available in three aquarium stores in the Washington D.C. area. We found all of these
specimens (n=4) to be highly toxic with palytoxin or palytoxin-like compounds (range 0.5–3.5 mg
crude toxin/g zoanthid). One of the most potent non-protein compounds ever discovered is
present in dangerous quantities in a select species of zoanthid commonly sold in the home
aquarium trade.

12. Boiling water + Palytoxin = ER
This interesting article was published on March 4th, 2012.
By Jake Adams, from RefBuilders:
"Palythoa toxin from Palythoa and Zoanthus polyps is widely known to be one of the most
poisonous substances in the natural world, gram for gram. Armed with this knowledge a well-
informed aquarist suited up for Palythoa removal duty from one of his aquarium rocks with gloves
to protect his hands, safety glasses to protect his eyes but he made one crucial mistake that almost
cost him his life.
In a near fatal mis-judgement, this aquarist went to scraping and brushing the Palythoa in a
utility sink using hot water, thereby steaming the Palytoxin from the undesirable zoanthids and
vaporizing the noxious chemical straight into his unprotected lungs. Half an hour of breathing in
aerosolized palytoxin and home-reefer wasn’t feeling so hot, an hour later he was headed to the
emergency room where he began coughing blood and was nearly paralyzed.
Despite having the foresight to print out information about zoanthid and palytoxin to take
with him to the hospital, the doctors there were nearly helpless to rescue him. We’re not sure what
worked but in the end the would-be Palythoa remover nearly lost his life by protecting only 2/3 of
himself from the dangers of palytoxin, although we do know not if he has yet been released from
the hospital.
The moral of the story is to not inhale the palytoxin steam that is created when you steam
Palythoas with hot water, or to not vaporize them in the first place. The palytoxin from our
aquarium zoanthids should never be underestimated, no wonder it was first isolated from zoanthids
that Hawaiians called the “Seaweed of Death from Hana”.”

13. Toxic airborne poison from aquarium coral nearly kills Texas family
April 30, 2018 By Fiza Pirani, The Atlanta Journal-Constitution
Chasity Ahman of Cedar Park, Texas, is warning others after a coral in her saltwater
aquarium nearly killed her and her family. While cleaning her fish tank Thursday, she
noticed “these little, cute ... button polyps” growing on a rock and used a toothbrush to
scrape off some algae on the coral, called palythoa.
"Within an hour, we were all feeling kind of different," Ahman said. The symptoms were
worse than the flu. "We couldn't get out of bed. I couldn't answer the door. I couldn't
force myself out of bed,” she said about the next morning. Once they made it to the
hospital, even the doctors were at a loss.
When Ahman brushed the pretty palythoa, a coral in the zoanthid species commonly
bought anywhere saltwater fish are sold, the coral released a toxin called palytoxin,
which experts consider one of the deadliest poisons in the natural world. According to
Discover Magazine, one gram of the poison can kill a hundred million mice.
This isn’t the first time the dangers of airborne poison from zoanthids has made
headlines. Earlier this week, a Canadian man handling Australian zoanthid coral from
tank to tank said the poison was released into the air and left him and his entire family
of seven hospitalized. Another family of seven in Australia was hospitalized when a
nearby coral formation released the palytoxin.

14. Abrin – A ricin relative
Origin- Abrus precatorius
A climbing legume in the Fabaceae family
(lentils, peanuts, and peas) [Ricinus
communis is in the Euphorbiaceae family]
Commonly called Jequirity, Rosary Pea,
Precatory bean, Indian Licorice
The abrin toxin in concentrated in the
seeds

15. Abrin – A ricin relative
Individual beads are used in jewelry
making
If the strand breaks, beans can become
detached
Free beans are attractive for children and
pets, who can mistake them for candy
Ingestion is the most common form of
exposure
Image from: http://1.usa.gov/hRR0MH
Abrin is a 64 kDa glycoprotein
composed of A and B chains (very
similar to ricin)
The B chain is a lectin-like
polypeptide with binding affinity for
cell surface carbohydrates
The A chain contains the toxic moiety
with N-glycosidase activity
The A and B chains are joined by a
disulfide bond
Mechanism – Inhibits protein
synthesis via the same mechanism as
ricin! Essentially the same type of
toxin, but not as “popular” as ricin.