One of the trucks involved in the crash was hauling hazardous materials, which spilled out of the truck onto the roadway following the crash.
Indiana State Police said one semi hit two other tractor-trailers which were stopped due to an earlier crash.
Both lanes were immediately closed and remain so as clean up continues.
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At last checked, all of the southbound lanes on I-65 are closed.
Eventually, the truck caught fire, posing what police called an "explosion risk" and prompting officials to issue a non-mandatory evacuation of the surrounding areas. ISP said they have yet to determine what if any charges will be brought against the driver that caused the crash Wednesday.
Westbound traffic was being diverted off I-80/94 at Grant Street, and eastbound traffic was being diverted off at Cline Avenue.
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At around 10:30 a.m. the left lane reopened.
The Indiana Department of Environmental Management is cleaning up the chemicals, WLFI-TV reported. A private environmental cleanup company was also on hand to help offload the contents of the leaking trailer.
Both lanes are expected to be reopened by the afternoon.
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They also blocked main road for traffic, demanding to hang the culprit in public so that no such incident will happen in future. A spokesman for the Punjab provincial police said paramilitary troops had been called in to restore order.