Venomous Frogs Are Super-Awesome,

But They Are Not Going To Kill You (I

Promise)
By Christie Wilcox | August 7, 2015 12:05 pm

In the first chapter for my upcoming book Venomous (due out in 2016), I excitedly
explain how nearly all the sundry branches of the tree of life have venomous leaves. Im
simply enthralled by the incredible diversity of venomous animals (and plants!) on this
planet, from the tentacle-wielding jellies to the spiny scorpionfishes and, of course, the
oft-feared and misunderstood snakes, spiders, and scorpions. But until today, there is
one group that could not boast a single venomous member: the anurans, commonly
known as frogs and toads. While there are plenty of poisonous ones, no one has ever
found a venomous frog that is, until now.

I know scientists are brazen, but Im pretty sure that lead author Carlos Jared wouldnt hold this venomousCorythomantis
greeningi with his bare hands if it were indeed deadly.
Photo by Carlos Jared / Current Biology

Venomous animals are natural biochemists that take toxic to a whole new level. While it
is true that venoms and poisons are both toxins, the two terms are not interchangeable.
All toxins cause harm in low doses; Poisons are substances that cause such harm
through ingestion, inhalation or absorption. To earn the title of venomous, on the other
hand, an animal has to do more than just have toxins they have to have a means of
wounding their intended victims to force those toxins upon them. That wounding can
be caused by any weapon of choice; jellies and other members of the phylum

Cnidaria use specialized stinging cells that shoot out hollow threads in less than a
microsecond to deliver their potent venom. Snakes and spiders use fangs, the venomous
fishes use spines, and the newest members of the venomous family the
frogs Aparasphenodon brunoi and Corythomantis greeningi use their spiky heads.
In a paper published yesterday in Current Biology, Carlos Jared and his colleagues
describe two species of frogs which sport specialized bones that they use to deliver toxic
skin secretions, making them the first venomous frogs ever described. The frogs
themselves are not new species scientists have known about them for some time
but no one had noticed that they use spiny projections from their skeleton to
envenomate would-be predators.

The two venomous frogs and their spiny skulls which are likely used to envenomate would-be attackers.
Figure 1 from Jared et al. 2015

Not suprisingly, such an incredible find has drawn quite a bit of media attention, some
of which is pretty well done. But, as you might have guessed by the title, this post isnt in
praise of the papers coverage. Come on, journalists this frog isnt going to kill you
with a head butt. They dont have a kiss of death. They arent deadly, and the toxin
they deliver with a fling of their cranium isnt enough to kill 80 people.
Yes, its true that the the skins of these frogs contain potent toxic cocktails of proteins.
Scientists often measure toxin potency by what is referred to as median lethal dose, or
LD50 the dose which kills half of the individuals (usually mice) who receive it. The
LD50 of the venom from of A. brunoi when injected into the bodies of a mice (a route
referred to as intraperitoneal) was 3.12 g for venom from the head, and 4.36 g for
venom from the body. That was about ten times more lethal than the same venoms
from C. greeningi (the LD50s of which were both roughly 50 g). Since that dose was in
mice that ranged from 18 to 20 grams in weight, we can calculate a milligrams per
kilogram of body weight toxicity (a standard unit for comparison) which ranges from
0.16 to 0.24 mg/kg for A. brunoi and from 2.5 to 2.9 mg/kg for C. greeningi. Those are
some pretty potent venoms, but theyre not anywhere near deadly enough to be of
concern to us.
The news reports seem to be extremely excited about the fact that the authors
compared the frog venoms to pit viper venom, with the journalists harping on the idea
that A. brunoi venom is about 25 times as potent as Bothropsspecies. But the authors
should have known better than to make such a specious comparison. There are more
than 30 different species of Bothrops, each with its own venom potency; its not fair to
lump them all together and assign some random mean value. Its especially not fair to
take a subset of less than half of those species (which doesnt even include the most
potent one!) and call it an average for the genus. Bothrops asper, the most notorious of
the genus known by the common name fer-de-lance, has an intraperitoneal LD50
of 0.469 mg/kg certainly stronger than C. greeningi, though admittedly half the
strength of A. brunoi.Meanwhile, Bothrops itapetiningae, the So Paulo lancehead,
injects a weak 74.4 mg/kg venom, which is a staggering 437 times weaker than the
strongest frog!
Of course, potency isnt everything. It doesnt matter if it will take less than 15
milligrams to kill you if you will never, ever, ever get 15 milligrams into your system.
One of the weaknesses of this study is that the authors were unable to determine just
how much venom is delivered during an encounter. As you can see of the photo of the
live frog some spines are coated with secretion and others dont seem to be, explained
Edmund Brodie, one of the papers co-authors. The amount of secretion produced is
copious but we dont have an estimate of how much is carried on a spine. This was due
to the method of venom collection, where frogs were massaged while in a container of
water to cause them to secrete venom into the fluid. The secretions from multiple frogs
were pooled and combined into one crude venom so there isnt even a venom per frog
estimate. But Bryan Fry, a venom scientist with the University of Queensland who was
not a part of this study, estimates the maximum dose from a single frog would be less
than 100 micrograms, and likely significantly less than that.

Even if we take the high end, and say 100 micrograms per frog, youd have to be stung
by about 128 frogs to receive the LD50 dose from the head of A. brunoi. Even if you give
the frogs ten-fold more toxin an entire milligram it still would take over a dozen of
the animals to reach the LD50. A full-grown Bothrops asper, on the other hand, may
have more than 1500 mg of its venom at the ready. Which means while youd have to
pull every drop of venom from dozens to hundreds frogs to hit that median lethal dose,
each fer-de-lance is carrying enough venom to inject its LD50 dose into almost 720
people.
But why the comparison to Bothrops, anyway? Theyre nowhere near the most potent
snake. Oxyuranus scutellatus, the coastal taipan, has an intraperitoneal LD50 of 0.009
mg/kg, and can be milked for almost 900 mg of that venom in one sitting! So they can
be slithering around with enough venom to inject more than a thousand
people with an LD50 dose. And to put the frogs into perspective of non-snake venoms,
the harvester ant,Pogonomyrmex maricopa, boasts an impressive LD50 of 0.12 mg/kg,
while both the ant and frog venoms are weaksauce when compared to the 0.01 mg/kg
venom of the box jellyfish, Chironex fleckeri.
And if you really want to talk deadly, did you know that tens of millions of
people around the world face a toxin every year thats more than 140,000 times as
potent than the strongest venom from A. brunoi? You might have heard of it its one
of the nasty molecules from the bacterium Clostridium botulinum, better known by its
medical name Botox. My point is, knowing how strong a toxin is doesnt tell us as
much information as you might think.

According to the legend in the paper, this figure shows edematogenic activity of A. brunoi venom. How did the mice in the 8 g
and 32 g groups survive for three days? Oh, yeah, the subcutaneous LD50 is much, much weaker.
Figure 2 from Jared et al. 2015

Of course, thats assuming the toxicity is accurate and meaningful to the route of
administration, and to that end, theres something very important to notice in the data.
If you look at the experimental protocols and results for the other two studies they did
with mice whether the venoms induced swelling or caused the animals to fuss with
an envenomated area they injected mouse paws with a range of doses of venom and
watched for up to 72 hours to see how things progressed. All of which seems perfectly
reasonable, until you look closer at those doses: they injected mice with 0.125 to 32 g.

The dose that killed half of the mice they injected, remember, was 3.12 g so how did
a dozen mice survive 72 hours with 2.5 10 times that amount of venom injected into
their paw?
According to Brodie, the effect on mouse mortality is very different depending on the
site of injection. And hes right injections under the skin (subcutaneous) can have
different LD50s that ones into the body (intraperitoneal). Brodie also noted that any
dose above the LD50 would kill all mice, thus based on the fact that mice received 32
g of venom in the paw and survived at least 3 days, the subcutaneous LD50 is over ten
times less potent than the intraperitoneal one. Which really makes the comparison
toBothrops even sillier, since the spikes in these frogs are tiny theyre barely going to
break the skin, and certainly arent going to allow for venom delivery into the body
cavity of any animal, especially not large, thick-skinned ones like us. So what really
matters isnt the intraperitoneal LD50 its the subcutaneous one, which Brodie says
the team didnt attempt to figure out.
If you still want to compare to the snakes, I couldnt find a subcutaneous LD50
for Bothrops asper, but Bothrops jacaraca has a subcutaneous LD50 of 7 mg/kg. The
tiger rattlesnake (Crotalus tigris) has a subcutaneous LD50 of 0.21 mg/kg, and the
inland taipan, Oxyuranus microlepidotus, is ten-fold stronger with a subcutaneous
LD50 of only 0.025 mg/kg!
Regardless of how potent the venoms are, focusing on how many people a gram of the
toxin could kill or calling the frogs lethal or deadly when theres no evidence that
theyve actually killed anyone completely misses the point. I even asked the authors, and
Brodie said there isnt a single known case of them killing a hopeful predator, let alone a
person. This just gives the impression the frogs are ridiculously toxic, says Fry,
which isnt why theyre awesome. These are the first venomous frogs known to
science, and theyre probably not alone. If their spikey skeletons have gone overlooked
for so long, then who knows how many potently poisonous frogs are actually venomous!
Thats an incredibly huge finding, or as Fry told The Guardian,unprecedented would
actually be an understatement.
When Fry spoke to at least one reporter, he cautioned about focusing on toxicity
apparently, his advice fell on deaf ears. She chose not to include it, feeling perhaps that
it detracted from the coolness of the story. Which it very much does not. It is an amazing
discovery! he wrote. Other venom scientists were equally frustrated. I made exactly
the same point!!! commented Nicholas Casewell, a venom scientist from the Liverpool
School of Tropical Medicine. He went on to say that the comparison
with Bothrops was the only part of that paper he didnt like.
Venomous frogs are way too awesome to be bogged down by lazy comparisons and
ridiculous hyperbole. These little tree frogs deserve to be celebrated as the fascinating
discoveries they are, not vilified as the killers we might wish them to be. Theyve been
considered venomous for one day, and already, were calling them deadly and a suite
of other fear-mongering terms. Cant we talk about venomous animals without making it
all about whether theyre going to kill you? And even more to the point, with all the
potential pharmaceuticals being discovered in venoms nowadays, these little anurans

may turn out to be life-savers rather than murderers. So how about we relax on the
toxicity talk and just enjoy them for the wonders they are, eh guys?

Citation: Jared et al. (2015) Venomous Frogs Use Heads as Weapons.Current Biology,
In Press, doi: 10.1016/ j.cub.2015.06.061
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