Table 5.
Results of published studies that examined neonicotinoid insecticides for developmental neurotoxicity.
| Test item; dose levels; reference | Test system and design | Type of investigation | Parameter | Effect – males | Effect – females | |
|---|---|---|---|---|---|---|
| Imidacloprid and acetamiprid;0.5–100 μM; Kimura-Kuroda et al. (2012) | Cerebellar granule cells from PND 1 rats | Primary cell culture | Ca2+ influx as indicator of physiological activity nAChR antagonists | Ca2+ influxes evoked by ACE, IMI and nicotine at >1 μM in small neurons that expressed α3, α4 and α7 nAChR subunits; Response inhibited by mecamylamine, α-bungarotoxin and dihydro-β-erythroidine | ||
| Imidacloprid 0 and 337 mg/kg; Abou-Donia et al. (2008) | Sprague–Dawley rat;Single i.p. dose on GD 9;Tests on PND 30 | F1 generation: ∼20 pups from 5 litters/dose level | Inclined plane, beam-walking and forepaw grip | Deficits inclined plane test and grip time | ||
| Plasma cholinesterase; Histopathology, AChE and GFAP activity in motor cortex and dentate gyrus | Increased plasma ChE (males) Brain-region-specific AChE and GFAP (motor cortex (layer III) and hippocampus (CA1, CA3, and dentate gyrus)) | |||||
| Clothianidin; 0, 2, 8, and 24 mg/kg; Ozdemir et al. (2014) | Wistar rat; Treated daily by gavage from PND 7 | F1 generation (6 male pups from each of 4 litters/dose level | Morris water maze | No effect on cognition at any dose; Less time in target quadrant in the probe test at high dose | Not tested | |
| mRNA: N-methyl d-aspartate 1, muscarinic receptor M1, synaptophysin and growth-associated protein 43 in the hippocampus | No effect at any dose | Not tested | ||||
| Clothianidin; 0, 0.003, 0.006, and 0.012% in diet; Tanaka (2012b) Achieved doses (mg/kg/d): Control: 0 Low: 4.37–15.21 Mid: 8.94–30.60 High: 18.48–60.26 (pre-mating – lactational values) | CD1 mice; Treated 5 weeks of age (F0) to 11 weeks of age (F1) | P generation:Pre-mating, gestation, lactation | BW, food consumption | No effects | No effects | |
| P generation, Neurobehavioral(8-weeks old) | Movement, 8 weeks; 8 parameters a analyzed for one 10-min session | Average time of movement, no. rearing, and rearing time, Increased trend b | No effects | |||
| F1 generationReproductive parameters | Litter size, weight at birth; Sex ratio | No effectsNo effects | No effectsNo effects | |||
| F1 generationLactation period | BW – low doseBW – mid doseBW – high dose | Increased PND 4Increased PND4, 7No effects | Increased PND4, 7Increased PND4, 7Increased PND 4 | |||
| F1 generationNeurobehavioral during lactation | Surface righting (PND 4 and 7)Negative geotaxis (PND 4 and 7)Cliff avoidance (PND 7)Swimming head angle (PND 7 and 14)Swimming direction and limb movement (PND 7 and 14)Olfactory orientation (PND 14)-Time-Route | No effectsNo effectsNo effectsAccel., PND 7, mid doseNo effects-Accelerated mid dose-No effects | Accel., PND 4, low doseAccel., PND 7, low doseNo effectsAccel., PND 7, low and mid doseNo effects-No effects-Delayed, mid dose | |||
| F1 generationNeurobehavioral post-lactation | Movement, 3 weeks, 8 parameters a for one 10-min sessionBiel Multiple-T water maze, 7 weeks; 1 trial/d for 3 dMovement, 8 weeks; 8 parameters a analyzed for one 10-min sessionMovement, 9–10 weeks; 8 parameters a analyzed for twelve 10-min intervals (=120 min session). Longitudinal pattern c of intersession interval | No effectsNo effectsIncreased trendb movement time; Decreased, mid dose average rearing time.Decrease, low dose in 1 of 8 parameters at only 1 of 12 time intervals (no pattern of effect); No effect on longitudinal pattern | Increased trendb in no. rearingsNo effectsNo effects Decrease, mid dose in 2 of 8 parameters, each at only 1 of 12 time intervals (no pattern of effect); No effect on longitudinal pattern | |||
| Clothianidin; 0, 0.002, 0.006, and 0.018% in diet; Tanaka (2012a) Achieved doses (mg/kg/d): Control: 0 Low: 3.00–11.71 Mid: 8.81–32.72 High: 28.61–99.65 (gestation – lactational values) | CD1 mice; pregnant females; treated during gestation and lactation.F1 given control diet after weaning | P generation:gestation, lactation | BW, food consumption | Not applicable | No effects | |
| F1 generationReproductive parameters | Litter sizeWeight at birthSex ratio | No effectsNo effectsNo effects d | No effectsIncrease – mid dose.No effects | |||
| F1 generationLactation period | BW – low dose, BW – mid dose, BW – high dose | Increased PND4, 21Increased PND4, 7, 21Increased PND4, 7, 21 | Increased PND4, 7, 21Increased PND0 -21Increased PND4, 7, 21 | |||
| F1 generationNeurobehavioralduring lactation | Surface righting, PND 4 and 7Negative geotaxis, PND 4 and 7Cliff avoidance, PND 7Swimming head angle PND7 and 14Swimming direction, PND 7 and 14Olfactory orientation, PND14Movement, 3 weeks; 8 parameters for 10-min session | No effectsNo effectsNo effectsNo effectsNo effectsNo effectsIncreased avg. speed; trend test b | Accelerated low dose, PND 7No effectsNo effectsNo effectsAccelerated mid dose, PND 7Accelerated mid doseNo effects | |||
| F1 generationNeurobehavioral post-lactation | Biel Multiple-T water maze, 7 weeks; 1 trial/d for 3 dMovement, 8 weeks; 8 parameters a analyzed for one 10-min session.Movement, 9–10 weeks; 8 parameters a analyzed for twelve 10-min intervals (=120 min session). Longitudinal pattern of intersession intervals | No effectsNo effects7 parameters e , increased after 100 min. in 1 or 2 intervals, mid dose onlyNo effect on overall longitudinal pattern | No effectsDecrease, rearing time – mid doseNo effectsNo effect on overall longitudinal patterns | |||
a
Eight movement parameters were total distance (cm), no. horizontal activities, movement time(s), no. rearing, rearing time(s), average time of movement(s), average speed (cm/s), average time of rearing(s).
b
Author conducted a posteriori trend tests that were not planned according to Methods section. There was no statistical significance for the planned treated group comparisons with control for each of the eight movement parameters (described in previous footnote).
c
The longitudinal pattern was assessed with the profile analysis in the parallelism hypothesis test.
d
No statistically significant differences. The percent (%) males at the high dose (41.1%) were less than control (54.4%).
e
Parameters increased were total distance (110 and 120 min), movement time (120 min), average time in movement (110 min), rearing time (110 min), no. horizontal activity (120 min), average speed (100 and 110 min), average time of rearing but not average time of rearing (110 min).