A Superior Cervical Ganglion
B Coeliac Ganglion
C Superior Mesenteric Ganglion
D Inferior Mesenteric Ganglion
The coloured circles represent the paravertebral ganglionic
Note the complex interactions of sympathetic nerves from
various regions of the spinal cord.
Remember this diagram is highly simplified for clarity!!
use of high doses increases the likelihood that potentially
significant toxic effects will be identified. Findings of
adverse effects in any one species do not necessarily indicate
such effects might be generated in humans. From a conservative
risk assessment perspective however, adverse findings in
animal species are assumed to represent potential effects
in humans, unless convincing evidence of species specificity
Food and Agricultural Organization of the United Nations
This is not an exhaustive list.
When time allows more information will be added.
- Rodenticide - CAS No. 63333-35-7
is a new rodenticide for the control of commensal rodents. Doses
in excess of the LD50 (2 mg/kg in rats) will cause death within
8-12 hr and it is preceded by one to three episodes of
clonic convulsions with death usually due to respiratory
arrest. Multiple low doses or sublethal intoxication yields hind
leg weakness and loss of tactile sensation in rodents. Histopathology
of the brain and spinal cord of these
animals revealed a spongy degeneration of the white matter which
was shown upon ultramicroscopic examination to be intramyelenic
Ref: Fundam Appl Toxicol 1988 Nov;11(4):664-72
The toxicity and mechanism of action of bromethalin: a new single-feeding
rodenticide. by van Lier RB and Cherry LD.
Acaricide, Insecticide - CAS No. 122453-73-0
-- MRID No. 42770219
(1993)-- 90-Day oral toxicity rats.
NOAEL = 24.1 mg/kg/day. LOAEL = 48.4, based on
spongiform myelopathy in the brain and spinal
cord of male rats, decreased body
weight gain and increased relative liver weight in males and females,
increased absolute liver weight in females, and decreased hemoglobin
Federal Register: September 26, 2003. Chlorfenapyr; Pesticide
Tolerance. Final Rule.
ii. Subchronic Oral
Toxicity in Mice... Spongiform encephalopathy
was noted in the brain and myelin of the spinal
cord of both males and females receiving the 320 ppm treatment
level. The LEL is 14.8 mg/kg/day (80 ppm) for male mice and 40.0
mg/kg/day (160 ppm) for female mice, based on hepatic cell hypertrophy
in 20% of the test animals at this treatment level. The NOEL
is 7.1 mg/kg/day (40 ppm)... The RfD Committee also recommended
that a special developmental neurotoxicity study be conducted
based upon the effects of a spongyform myelopathy
vacuolation seen in the brain and spinal cord
of treated rats and mice. They concluded that the registrant should
also conduct a mechanistic study to determine the cause/relationship
of CNS/myelinopathic alterations to neurotoxicity (including developmental)...
Chronic-Term (greater than several months) Occupational/Residential
Dermal NOEL: 3 mg/kg/day (decreased body weight gains brain
lesions (vacuolation) and/or
scabbing of the skin in a 1 year neurotoxicity study in rats and
a chronic/carcinogenicity study in mice) Acceptable MOE = 1000
(includes FQPA Factor)
Ref: US EPA, Feb 12, 1998: Chlorfenapyr
- 129093: Health Effects Division Risk Characterization for Use
of the Chemical Chlorfenapyr.
. 066; 147076; "A Chronic Dietary Toxicity
and Oncogenicity Study with AC 303,630 in Mice" (L. Bernier,
Bio-Research Lab., Ltd., Quebec, Canada, Project # 84580, 8/22/94).
AC 303,630 (Batch AC-7504-59A, 94.5% purity) administered orally
in the diet to 65 CD-1 mice/sex/dose for 80 weeks at 0, 20, 120,
or 240 ppm (Males: 0, 2.8, 16.6, or 34.5 mg/kg/day; Females: 0,
3.7, 21.9, or 44.5 mg/kg/day). Reduced survival rate was noted
in high dose females (60% vs. 80%, p < 0.05). However, overall
survival rate of this group was more comparable to that of the
historical controls. Treatment with AC 303,630 resulted in reduced
mean body weight gain in high dose males and females and in mid
dose females (Males: 70% of control, p < 0.01, Females: 86% of
control, p < 0.05 for mid and high dose groups). Food consumption
was also reduced in mid and high dose animals.
Histopathology revealed vacuolation of the white matter of the
brain in animals treated at mid and high dose levels. Also, vacuolation
was detected in spinal cord sections
as well as optic nerve tissues in mice at
240 ppm. There was no evidence
of carcinogenicity. NOAEL (M/F) = 240 ppm [No adverse effect].
NOEL (M/F) = 20 ppm (2.8 and 3.7 mg/kg/day for males and
females, respectively; based on histopathological changes in the
brain, optic nerve and spinal cord). acceptable (Leung, 7/24/96)
-- NEUROTOXICITY ** 061; 147070; "A One-Year
Dietary Neurotoxicity Study with AC 303,630 in Rats"; (J.A.
Foss; Argus Research Laboratories, Inc., Horsham, PA; Study No.
101-019; 5/10/94); AC 303,630 technical (purity: 94.5%) was administered
in the diet to 25 animals/sex/group at doses of 0, 60, 300, and
600 ppm for up to 52 weeks ((M)-0, 2.6, 13.6, 28.2 mg/kg/day,
(F)-0, 3.4, 18.0, 37.4 mg/kg/day). Surviving animals were observed
for an additional 16 weeks of a recovery phase. No treatment-related
effects were noted in the functional observational battery or
the motor activity evaluation. In the neurohistopathology,
myelin sheath swelling of the spinal nerve roots was evident in
the males of the 600 ppm treatment group after 13 and 52
weeks of treatment. Extensive vacuolar myelinopathy
was noted in the brain and spinal cord of the 300 and 600 ppm
males after 52 weeks of treatment. These effects were no
longer present after the 16 week recovery period. No treatment-related
lesions were noted in the females. No adverse effects were evident.
NOEL: (M) 60 ppm (based upon the incidence of extensive vacuolar
myelinopathy in the central nervous system); (F) 600 ppm;
NOAEL: 600 ppm (based on recovery). Study acceptable. (Moore,
-- SUBCHRONIC STUDIES
** 010, 031; 125163; "AC 303,630: A 13 Week
Dietary Toxicity Study in the Albino Rat", J.E. Fischer;
821; Rat; American Cyanamid Co., Agricultural Research Division,
Toxicology Department, Princeton, NJ; Study No. T-0316; 4/8/93;
AC 303,630 Technical (purity: 93.6%); 20 animals/sex/group; Doses:
0, 150, 300, 600, 900, 1200 ppm (M: 0, 10.9, 22.0, 44.9, 69.5,
92.2 mg/kg/day, F: 0 11.7, 24.1, 48.4, 72.5, 97.5 mg/kg/day),
in the diet, 13 weeks; No treatment-related mortality; Clinical
Observations: red. body wgt. gain (M,F-900, 1200 ppm), red. food
consumption (M-600 ppm and up); Ophthalmology, Urinalysis: no
treatment-related effects; Hematology: red. hematocrit (M,F-1200,
F-900 ppm), red. hemoglobin (M,F-1200, F-600, 900 ppm), red blood
cells (M,F-1200, F-900 ppm), Clinical Chemistry: incr. BUN (M,F-1200
ppm, week 6, M-1200 ppm, week 13), incr. alk. phosphatase activity
(M,F-900, 1200 ppm, week 13); Necropsy: incr. mean abs. liver
wgt. (F-600 ppm and up), red. abs. kidney wgt (M,F-900, 1200 ppm),
incr. abs. spleen wgt. (M,F-900, 1200 ppm), incr. rel. liver wgt.
(M,F-600, 900, 1200, M-300 ppm), increased relative spleen weight
(M,F-900, 1200 ppm); Histopathology: spongiform
myelopathy in brain, spinal cord (M-(2/20), 1200, 900 ppm, (1/20),
600 ppm), lesion present in sciatic nerve (M-(1/20), 1200
ppm), lymphoid cell infiltrate in kidneys (M,F-900, 1200 ppm);
Target organ: central nervous system;
Adverse Effect: spongiform myelopathy in
the nervous system; NOEL: (M) 300 ppm (occurance of spongiform
myelopathy in the nervous system of the 600 ppm group) (F)
300 ppm (based on increased mean abs. liver wgt. in 600 ppm group);
(Study previously unacceptable, possibly upgradeable with submission
of GLP compliance and QA audit statements (Moore, 2/1/95)) requested
information submitted; Study acceptable. (Moore, 8/9/95)
24, 2001 - Summary
of Toxicological Data. California EPA.
Department of Pesticide Regulation. Medical Toxicology Branch.
Also available at: http://www.cdpr.ca.gov/docs/toxsums/pdfs/3938.pdf
- Insecticide, Fungicide, Propellant, EPA List 2 Inert
- CAS No. 75-45-6
mouse lowest published toxic concentration: 50 gm/m3/6 hour/43
week- intermittent Brain and Coverings: Other
degenerative changes: Spinal Cord. Other degenerative changes.
Behavioral: Alteration of classical conditioning. [Trudy Leningradskogo
Sanitarno-Gigienicheskogo Meditsinskogo Instituta. (Leningrad,
Ref: NIOSH. Registry of Toxic Effects. July
- Fungicide - CAS
Oral 1 year 95.3%,
Beagles, 0, 1, 10, 50 mg/kg/d, 6/sex/dose NOAEL 1 mg/kg/d LOAEL
10 mg/kg/d 10 mg/kg/d 8 Nasal dryness &. 8 Incidence and severity
of gastric lymphoid hyperplasia. 9 Myeloid to erythroid ratios
in bone &. 50 mg/kg/d 8 Nasal dryness and salivation % and &.
9 bwg in both sexes, but only significant in &. 9 Myeloid to erythroid
ratios in bone &. 9 Hematocrit, hemoglobin, RBC % and . 8 WBC
mid and high doses % and &. 8 Alk phos, cholesterol % and &. 8
Abs and rel liver weight % and 8 Incidence
of white matter vacuolation in brain and spinal cord
8 Incidence and severity of gastric lymphoid hyperplasia.
Note REG2003-12. Fluazinam. Pest
Management Regulatory Agency. Health Canada. Ottawa. October 27,
- Herbicide - CAS No. 142459-58-3
Chronic toxicity. A 1-year dog chronic
feeding study with a NOEL was 40 ppm [1.29 mg/kg/day in males
and 1.14 mg/kg/day in females] and a LOEL of 800 ppm [27.75 mg/kg/day
in males and 26.82 mg/kg/day in females] based on increased alkaline
phosphatase, kidney, and liver weight in both sexes, increased
cholesterol in males, decreased T2, T4 and ALT values in both
sexes, and increased incidences of microscopic
lesions in the brain, eye, kidney, spinal
cord, sciatic nerve and liver. A rat chronic feeding/carcinogenicity
study with a NOEL less than 25 ppm [1.2 mg/kg/day in males and
1.5 mg/kg/day in females] and a LOEL of 25 ppm [1.2 mg/kg/day
in males and 1.5 mg/kg/day in females] based on methemoglobinemia
and multi-organ effects in blood, kidney,
spleen, heart, and uterus. Under experimental conditions the treatment
did not alter the spontaneous tumor profile. In a mouse carcinogenicity
study the NOEL was less than 50 ppm [7.4 mg/kg/day] for males
NOEL was 50 ppm [9.4 mg/kg/day] for females and the LOEL was 50
ppm [7.4 mg/kg/day] for males and the LOEL was 200 ppm [38.4 mg/kg/day]
for females based on cataract incidence and severity. There was
no evidence of carcinogenicity for flufenacet in this study.
Ref: Federal Register. June 23, 1998. Pesticide
In an acute rat neurotoxicity study
the NOEL was less than 75 mg/kg and the LOEL was 75 mg/kg/day
based on decreased motor activity in males. In a rat subchronic
neurotoxicity study the NOEL was 7.3 mg/kg/day in males and 8.4
mg/kg/day in females and the LOEL was 38.1 mg/kg/day in males
and 42.6 mg/kg/day in females based on microscopic
lesions in the cerebellum/medulla and spinal cords.
Ref: Flufenacet. Pesticide Fact Sheet.
US EPA, April 8, 1998.
Acid - Rodenticide
CAS No. 144-49-0
and fluorocitric acid toxicity is often characterized by seizures,
however the mechanism of this activity is unknown. Intrathecal
(i.t.) injection of fluorocitrate in mice resulted in seizures
after an average latency of 15 s, while intracerebroventricular
(i.c.v.) injection produced seizures after 36.5 min, and required
higher doses to achieve this effect. This
indicates the probable site of fluoroacetate and fluorocitrate
neurotoxicity is the spinal cord. To mimic citrate accumulation,
characteristic of fluoroacetate and fluorocitrate poisoning, citric
acid was injected i.t. and also found to produce seizures. The
structurally unrelated compounds EDTA, EGTA, glutamic acid and
lactic acid also produced seizures identical to fluorocitrate.
The ability of these compounds to chelate Ca2+ correlates well
with their ability to cause seizures when administered i.t. and
coadministration of calcium greatly attenuated
the neurotoxicity of these compounds as well as fluoroacetate
and fluorocitrate. In contrast, Ca2+ was unable to inhibit
seizures elicited by strychnine, suggesting calcium's ability
to inhibit chelators of divalent cations is not due to a general
anticonvulsant effect. These results suggest that changes in Ca2+
concentration in the spinal cord may be responsible for some forms
of seizure activity.
Hornfeldt CS, Larson AA (1990). Seizures induced by fluoroacetic
acid and fluorocitric acid may involve chelation of divalent cations
in the spinal cord. Eur J Pharmacol. 1990 Apr 25;179(3):307-13.
- Acaricide, Insecticide -
CAS No. 371-86-8
ORGANOPHOSPHORUS CMPD CAN PRODUCE PERMANENT PARALYSIS DUE TO /PRC:
SECONDARY/ DEMYELINATING PROCESS OF SPINAL CORD... DEMYELINATION
IN MAN HAS BEEN ATTRIBUTED ONLY TO MIPAFOX, AGENT
NOT USED IN UNITED STATES. [Hamilton, A., and H. L. Hardy. Industrial
Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc.,
TOXNET profile for Mipafox from Hazardous Substances Data Base.
Short term clinical
and neuropathological effects induced by tri-ortho-tolyl-phosphate
(78308) (TOTP), diisopropyl-fluorophosphate (55914) (DFP), phenyl-saligenin-phosphate
(4081236) (PSP), mipafox (371868), malathion (121755), dichlorvos
(62737), and carbaryl (63252) were studied in rats. Male Long-Evans-rats
were administered 300 to 1000mg/kg TOTP or 300 to 2000mg/kg malathion
orally, injected intramuscularly with 5 to 24mg/kg PSP, injected
subcutaneously with 1 to 3mg/kg DFP, or injected intraperitoneally
with 3 to 30mg/kg mipafox or dichlorvos or 30 to 160mg/kg carbaryl.
The rats were also treated with atropine-sulfate to protect against
cholinergic symptoms. Selected rats were killed 4 hours after
DFP, PSP, mipafox, dichlorvos, and carbaryl or 48 hours after
TOTP and malathion and the brains and spinal cords were removed
and assayed for acetylcholinesterase (AChE) and neurotoxic-esterase
(NTE) activity. The remaining rats were weighed and evaluated
on a functional observational battery (FOB) that measured motor
activity and responses to being handled or approached 1, 7, 14,
and 21 days after dosing. The rats were then killed and the brains,
spinal cords, and tibial nerve branches leading to the gastrocnemius
muscle were examined for histopathological changes. The highest
doses of all compounds except PSP induced transient cholinergic
symptoms and caused 8.3 to 61% mortality within 48 hours. The
highest doses of TOTP, DFP, and malathion significantly decreased
body weight after 14 days. All compounds caused dose related inhibitions
of brain and spinal cord AChE and NTE activity. DFP was the most
potent and PSP the least potent. All compounds induced significant
changes in FOB parameters related to behavioral and central nervous
system excitability 21 days after dosing. Mipafox, PSP, dichlorvos,
and carbaryl induced these changes 1 day after dosing. TOTP, DFP,
PSP, and mipafox caused mild to moderate myelinated
fiber degeneration in the rostral fasciculus gracilis 21 days
after dosing. Mipafox was the most
potent. DFP also induced Wallerian like degeneration in
the tibial nerve branches. Dichlorvos, malathion, and carbaryl
did not cause any neurological changes. The authors conclude that
some cholinesterase inhibitors cause behavioral changes even after
cholinergic signs are no longer evident.
Ref: Ehrich M et al. (1993). Short-Term
Clinical and Neuropathologic Effects of Cholinesterase Inhibitors
in Rats. Journal of the American College of Toxicology, Vol. 12,
No. 1, pages 55-68. As cited at Toxnet.
White matter in the dorsal, medial area of the spinal cord. It
forms the entire dorsal column in the lumbar and sacral levels
and the medial division of the dorsal column in the thoracic and
cervical regions. It carries sensory information from the lower
extremities. In the thoracic and cervical regions it is located
between the fasciculus cuneatus and the dorsal median fissure.
In the lumbar and sacral regions it is found between the dorsal
horn and the dorsal median fissure.